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Temperature-induced cardiac remodelling in fish

Temperature-induced cardiac remodelling in fish © 2017. Published by The Company of Biologists Ltd | Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 REVIEW 1 2 1 3, Adam N. Keen , Jordan M. Klaiman , Holly A. Shiels and Todd E. Gillis * ABSTRACT the wild (Cortemeglia and Beitinger, 2005; Sidhu et al., 2014) and can experience a 10°C change in temperature between winter and Thermal acclimation causes the heart of some fish species to undergo summer (López-Olmeda and Sánchez-Vázquez, 2011). Marine significant remodelling. This includes changes in electrical activity, species, such as tunas, also experience temperature changes energy utilization and structural properties at the gross and molecular seasonally (from 11 to 24°C) associated with oceanic migrations, level of organization. The purpose of this Review is to summarize and acutely (>10°C change) when diving through the thermocline the current state of knowledge of temperature-induced structural (Boustany et al., 2010). Although a change in temperature will affect remodelling in the fish ventricle across different levels of biological the function of all organs, the function of the heart is especially organization, and to examine how such changes result in the important because of its role in moving oxygen, metabolic modification of the functional properties of the heart. The structural substrates and metabolic byproducts around the body, and remodelling responseisthought tobe responsible forchanges in cardiac 2+ therefore supporting active biological processes. Thus, many fish stiffness, the Ca sensitivity of force generation and the rate of force have mechanisms that preserve cardiac function across seasonal generation by the heart. Such changes to both active and passive temperature changes. properties help to compensate for the loss of cardiac function caused by The purpose of this Review is to examine temperature-induced a decrease in physiological temperature. Hence, temperature-induced structural remodelling of the ventricle in the hearts of selected fish cardiac remodelling is common in fish that remain active following species. We build upon excellent original work (i.e. Vornanen et al., seasonal decreases in temperature. This Review is organized around 2005) and comprehensive reviews of cardiac plasticity in fish (e.g. the ventricular phases of the cardiac cycle – specifically diastolic filling, Gamperl and Farrell, 2004). Importantly, here, we review changes in isovolumic pressure generation andejection – so that theconsequences both the active and passive properties (see Glossary) of the fish heart of remodelling can be fully described. We also compare the thermal following prolonged temperature change. We discuss ways in which acclimation-associated modifications of the fish ventricle with those the remodelling preserves or improves function (physiological seen in the mammalian ventricle in response to cardiac pathologies and remodelling) and ways in which the remodelling may relate to exercise. Finally, we consider how the plasticity of the fish heart may be dysfunction (pathological remodelling). Indeed, one of the interesting relevant to survival in a climate change context, where seasonal aspects of thermal remodelling in the fish heart is that it involves temperature changes could become more extreme and variable. changes that are similar to those observed during both physiological KEY WORDS: Cardiac function, Cardiac histology, Cardiac and pathological remodelling in mammalian hearts (see Dorn, 2007; remodelling, Connective tissue, Thermal acclimation Keen et al., 2016; Klaiman et al., 2011; Klaiman et al., 2014). We acknowledge that other aspects of fish heart function change with Introduction thermal acclimation, most notably the electrical properties. Pacemaker Ectothermic animals living in temperate environments can output can be reset, partly as a result of temperature-related changes in experience significant, long-term changes in ambient temperature. electrical excitability (Aho and Vornanen, 2001; Ekström et al., These seasonal fluctuations influence every level of biological 2016). Electrical excitability itself is modulated by temperature- function as a result of the universal effect of temperature on dependent shifts in ion channel densities and/or isoform switches molecular interactions. Consequently, biochemical, physiological which can vary between species and life histories (Vornanen, 2016; and biomechanical processes are all affected by changes in Badr et al., 2016). temperature. However, a number of ectothermic species, including In this Review, we focus on ventricular remodelling, primarily some fish, remain active across the seasons. These fish species in two species – rainbow trout and zebrafish. Cardiac remodelling include salmonids such as rainbow trout (Oncorhynchus mykiss), in the trout has been extensively studied and, as a cold-active which, depending on the strain, can remain active at temperatures species, its heart develops robust cardiac outputs (see Glossary) ranging from ∼4 to 24°C (Anttila et al., 2014; Elliott and Elliott, across a range of temperatures. We also discuss recent work on 2010; Rodnick et al., 2004). Members of the minnow family, such cardiac remodelling in the zebrafish – a species that has become as the zebrafish (Danio rerio), also have broad thermal tolerances in a popular model for understanding the development and regenerative capabilities of the vertebrate heart. With >30,000 extant species of fish (Nelson, 2006), the possible remodelling Division of Cardiovascular Science, School of Medicine, Faculty of Biology, phenotypes are abundant. We do not attempt to cover all of these in Medicine and Health, University of Manchester, Manchester, M13 9NT, UK. Department of Rehabilitation Medicine, University of Washington, Seattle, WA this Review, however, we include key studies on other fish species 98109, USA. Department of Integrative Biology, University of Guelph, Guelph, such as tunas, cod, flat fish and carp, where appropriate. A key aim Ontario, Canada N1G 2W1. of this Review is to show how thermal remodelling of active and *Author for correspondence ([email protected]) passive properties work together to preserve cardiac function across temperatures. For this reason, we have divided the Review T.E.G., 0000-0002-8585-0658 into three main sections, each addressing one of the ventricular This is an Open Access article distributed under the terms of the Creative Commons Attribution phases of the cardiac cycle: diastolic filling, isovolumic pressure License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, generation and ejection. Through this approach, we hope to distribution and reproduction in any medium provided that the original work is properly attributed. Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 this Review focuses on the force-generating capacity of the myocardium rather than cycle frequency. Changes in cardiac force Glossary Active properties of the heart are often the inverse of rate changes and compensate (at least partially) Properties that affect muscle contraction, including rate of cross-bridge for the direct effect of temperature in altering cycle frequency. Acute 2+ cycling and sensitivity to Ca . cooling also increases blood viscosity, which directly affects Bradycardia vascular resistance and increases cardiac load (Graham and Farrell, A reduction in the rate of cardiac contraction. 1989; Graham and Fletcher, 1985). Although these effects of acute Cardiac contractility 2+ temperature are detrimental to contractile function, chronic exposure Ability of heart to contract and generate force when stimulated by Ca . Cardiac myofilaments results in compensatory changes that limit their consequences for Primarily composed of the actin thin filament and myosin thick filament cardiac output, as discussed later in this Review. and responsible for force generation in striated muscle. Cardiac output Acute effects on the myofilaments Blood volume pumped by the heart per unit time, calculated as the An acute decrease in the temperature of the vertebrate heart, product of contraction Hz and stroke volume. including those from mammals and fish, impairs contractile Cardiac stiffness Ability of the heart to resist stretching, determined by both the active and function, as the thin filaments in cardiac muscle have a reduced 2+ passive properties of the muscle. Inverse of compliance. sensitivity to Ca at lower temperatures, resulting in a loss of force- Cardioplegic generating capacity (Churcott et al., 1994; Harrison and Bers, 1990; Reduction in cardiac contractility. Stephenson and Williams, 1985). See Box 1 for an explanation of Chamber compliance 2+ the Ca -mediated activation of cardiac contraction. The cold- Inverse of stiffness, can be measured as the change in pressure for a 2+ associated decrease in Ca sensitivity in cardiac muscle has been given change in volume. reported in a variety of animals, including trout, frogs, mice, rats, Inotropic effects Affecting the force of contraction. rabbits, ferrets and ground squirrels (Churcott et al., 1994; Harrison Passive properties of the heart and Bers, 1989; Liu et al., 1993, 1990). Studies by Gillis et al. Non-contractile properties that affect the stiffness of the heart and (Gillis et al., 2005, 2000, 2003b; Gillis and Tibbits, 2002) show that influence the ability of the heart to relax and fill with blood between 2+ this decrease in Ca sensitivity following an acute reduction in heartbeats. This is affected by collagen composition and the sarcomere 2+ temperature is due to a decrease in the Ca affinity of cardiac protein titin. 2+ troponin C, which is the Ca -activated trigger for the muscle (see Q effects The change in rate of biochemical reaction that occurs with a 10°C Box 1). Although the cardiac muscle of trout and mammals behaves change in temperature. in a similar way in response to reduced temperatures, trout Ventricular trabeculae myofilaments (see Glossary) have several characteristics that Discretebundles or sheetsof musclewithin thespongy myocardiumoffish. 2+ illustrate the integrated and comprehensive nature of the thermal Box 1. Ca -mediated activation of the heart 2+ cardiac remodelling response. Ca is responsible for initiating and regulating the contraction of striated muscle. Following the firing of the sinoatrial node, also known as the For simplicity, we have structured the Review around cardiac pacemaker, cellular membranes of cardiac myocytes in the heart observations associated with cold acclimation. Historically, 2+ are depolarized, which causes the L-type Ca channels to open. As a responses to cold acclimation have been the main experimental 2+ result, Ca enters the cell and can interact directly with the interest (Bailey and Driedzic, 1990; Driedzic et al., 1996; Farrell, 2+ myofilaments. Ca influx can also activate the ryanodine receptors 1991; Haverinen and Vornanen, 2007; Keen et al., 1993, 1994; (RyRs) located in the membrane of the sarcoplasmic reticulum (SR). 2+ Lurman et al., 2012); however, with rising temperatures becoming a The SR is an organelle that stores and releases Ca in the myocyte. The 2+ activation of the RyRs causes the release of Ca from the SR into the global concern, there is increasing interest in the effect of warming 2+ 2+ cytosol in a process called Ca -initiated Ca release (CICR). CICR is (Farrell et al., 1996; Farrell, 2002; Keen et al., 2016; Klaiman et al., vital for the contraction of mammalian hearts but less so for fish hearts, 2011; Syme et al., 2013). Therefore, we have added a concluding 2+ 2+ as extracellular Ca influx delivers sufficient Ca to the myofilaments in section to discuss the specific implications of prolonged warm most fish species (see Shiels and Galli, 2014). The increase in cytosolic temperatures on fish heart function. 2+ 2+ Ca activates the actin thin filament when Ca binds to the troponin (Tn) 2+ complex through cardiac troponin C (cTnC). Ca binds to a binding site Acute temperature change and cardiac function in the N-terminus of the protein, which initiates a conformational change in the molecule that triggers a series of further conformational changes Acute effects on whole heart function through the other component proteins of the thin filament, leading to the Acute temperature change (minutes to hours) directly influences exposure of a myosin-binding site on the surface of actin (see Gillis and physiological processes in fish through Q effects (see Glossary) on Tibbits, 2002). As a result, a myosin head binds to the actin thin filament, reaction rates. As the temperature drops, the heart becomes resulting in the formation of a cross-bridge. The cross-bridge generates bradycardic (see Glossary; Keen et al., 1993), which is largely due force with the hydrolysis of ATP, and the myosin head flexes. The to a greater diastolic duration, with systolic duration less affected formation of force-generating cross-bridges along the contractile element leads to the shortening of the sarcomere and the contraction of the (Badr et al., 2016). The greater diastolic duration acts to maintain muscle during systole. As a result, blood is pumped out of the heart. cardiac output by increasing filling time, which can lead to an increase 2+ For the heart to relax, Ca is pumped back into the SR through the SR in stroke volume even though cardiac contractility (see Glossary), 2+ + 2+ Ca -ATPase or out of the cell through the Na /Ca exchanger, causing force production and cycle frequency are reduced at lower 2+ 2+ cytosolic Ca concentrations to decrease. This causes Ca to temperatures (Shiels et al., 2002; Vornanen et al., 2005). Changes disassociate from the actin thin filament, resulting in the inhibition of in cycle frequency (i.e. heart rate; as reviewed by Vornanen, 2016) further cross-bridge formation. Inactivation of the cross-bridge cycle enables the myocardium to relax and then fill with blood during diastole. directly alter cellular processes within the heart, independent of temperature. While this is of prime importance to cardiac function, Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 allow the heart to remain functional over a range of physiological possibly on the I window current (see Vornanen, 1998), which Ca 2+ temperatures, including low temperatures. Churcott et al. (1994) occurs when L-type Ca channels that have inactivated reopen demonstrated that trout cardiac actin-myosin ATPase activity was during the action potential plateau. As the action potential duration 2+ more Ca sensitive than that from rats when compared at their is extended during cooling, it can allow a larger I window current. Ca respective physiological temperature and pH (7°C, pH 7.2 vs 37°C, It is important to note that in some species, like bluefin tuna, the 2+ pH 6.78 for trout and rat, respectively). Moreover, the authors found drop in Ca influx during cooling is not completely compensated 2+ that the Ca concentration required by trout cardiac muscle for by the increased action potential duration. In these hearts, preparations to reach half maximal tension was approximately one- adrenaline, which is thought to be released during dives into cold 2+ tenth that of rat cardiac tissue when tested at the same experimental water, augments Ca influx through voltage-gated ion channels. 2+ 2+ temperature (Fig. 1). This higher Ca sensitivity of the trout cardiac This increased Ca influx combines with a prolonged action 2+ tissue is believed to be one mechanism that helps to offset the potential duration to restore force-generating Ca flux into the cardioplegic effects (see Glossary) of cold on the trout heart myocytes during temperature changes of >10°C (Shiels et al., (Blumenschein et al., 2004; Gillis et al., 2003a). These interactions 2015). 2+ will be discussed further in the section ‘Myofibril remodelling’. Although this trade-off between action potential duration and Ca 2+ influx can maintain adequate Ca influx to allow the fish to cope Acute effects on ion channel flux and the action potential with short-term changes in temperature, it is less effective during 2+ 2+ Acute cooling reduces the flux of Ca (I , the Ca current) prolonged thermal acclimation. Indeed, during chronic (days to Ca 2+ + through voltage-gated Ca channels into the myocyte (Fig. 2), weeks) cold exposure there is a remodelling of potassium (K ) which can directly reduce the contractility of the heart at cold channel expression that serves to reverse the increase in action temperatures. This is because I is the primary source of the potential duration. This is important, as a prolonged action potential Ca 2+ activating Ca that triggers cross-bridge cycling. In fish species that can be pro-arrhythmic and also may compromise electrical restitution 2+ utilize intracellular Ca stores of the sarcoplasmic reticulum (SR) (the recovery of an action potential as a function of the diastolic in the activation of muscle contraction [e.g. rainbow trout (Hove- interval). These temperature-induced alterations in the ion channels Madsen and Tort, 1998; Shiels and White, 2005); burbot (Lota lota; of the fish heart are discussed in detail in a recent review (Vornanen, Shiels et al., 2006b); yellowfin tuna (Thunnus albacares; Shiels 2016). Together, the effects of an acute decrease in temperature on et al., 1999); bluefin tuna (Thunnus orientalis; Shiels et al., 2011); electrical and mechanical function lead to a reduction in the force Box 1], the reduction in I has a cascading effect: a reduced of cardiac muscle contraction (inotropic effects; see Glossary), Ca 2+ amplitude of I reduces the trigger for SR Ca release, thus illustrating the need for temperature-dependent remodelling to Ca 2+ reducing the amount of Ca available to interact with the preserve the active pumping properties of the fish heart during myofilaments and initiate cross-bridge cycling. chronic temperature change. Some of the direct effects of reduced I during cooling can be Ca offset by other temperature-induced changes in the electrical Acute effects on the diastolic properties of the heart properties of the heart. For example, acute cooling increases the An acute temperature change also influences the resting, non-force duration of the ventricular action potential [e.g. rainbow trout generating properties of the heart by affecting the passive properties (Shiels et al., 2000); bluefin tuna (Galli et al., 2009); pink salmon of the myocardium. For example, an increase in temperature (Oncorhynchus gorbuscha) (Ballesta et al., 2012)]. This allows decreases the contribution of viscous tension, viscoelastic tension 2+ more time for Ca influx during the action potential plateau, and elastic tension to cardiac stiffness (see Glossary), resulting in 6.5 Membrane potential (mV) –80 –60 –40 –20 0 20 40 60 80 6.0 –1 5.5 5.0 –5 14°C 21°C 4.5 7°C 0 5 10 15 20 25 30 Temperature (°C) –7 2+ 2+ Fig. 1. Ca sensitivity of force generation by skinned ventricular fibres Fig. 2. Trans-sarcolemmal Ca flux varies in trout cardiac myocytes with 2+ 2+ over a range of temperatures. pCa is the Ca concentration required to acute temperature changes. Acute reductions in temperature reduce Ca flux 2+ generate half-maximum force. When compared at the same temperature, trout through L-type Ca channels in rainbow trout atrial myocytes. All values are 2+ ventricular fibres require 10 times less Ca than those from the rat to generate means±s.e.m. The values for I (pA) are normalized from the measured cell Ca −1 the same amount of force. Figure adapted from Churcott et al. (1994). capacitance to give the value in pA pF . Figure adapted from Shiels et al. (2000). pCa –1 Peak I (pA pF ) Ca Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 decreased passive stiffness (Mutungi and Ranatunga, 1998). 2.5 Together, the changes in the non-force-generating properties of 5°C the muscle caused by a change in physiological temperature 10°C 2.0 18°C represent a potential challenge for the maintenance of normal cardiac function. It is, therefore, not surprising that factors which 1.5 contribute to the passive properties of the heart, such as collagen content and composition, are modified in response to thermal 1.0 acclimation (Keen et al., 2016; Klaiman et al., 2011; Johnson et al., 2014). 0.5 Cardiac remodelling following chronic temperature change Evidently, acute temperature change is a challenge for maintained 0.075 0.175 0.275 0.375 0.475 0.575 0.675 cardiac function in fishes. Thus, prolonged temperature change Volume (ml) results in remodelling of all aspects of cardiac function. For example, in relation to the direct effects of acute cooling discussed Fig. 3. Thermal remodelling of ventricular compliance in the rainbow above, cold acclimation results in an increase in basal heart rate trout. Ex vivo pressure–volume relationships show increased passive stiffness (Haverinen and Vornanen, 2007; Keen et al., 1993; Lurman et al., of the whole ventricle following cold acclimation (5°C) compared with controls 2012), maximum stroke volume (Driedzic et al., 1996; Farrell, (10°C), and increased compliance following warm acclimation (18°C). Data points show the means±s.e. All lines are significantly different from each other, 1991; Lurman et al., 2012), maximum power output (Bailey and assessed via GLM. Figure is adapted from Keen et al. (2016). Driedzic, 1990; Lurman et al., 2012) and maximum cardiac output (Lurman et al., 2012), as well as a greater sensitivity to β-adrenergic stimulation (Keen et al., 1993). For excellent reviews of energetics influenced at the organ level by the pericardium and by the geometry and electrical activity associated with thermal acclimation in fishes and thickness of the ventricular walls. In fish, the ratio of spongy to see Driedzic and Gesser (1994), Vornanen et al. (2002) and compact tissue is also likely to contribute to cardiac compliance, with Vornanen (2016). Below, we focus on the active and passive compact myocardium being stiffer than spongy myocardium. changes associated with structural remodelling of the fish heart. Historically, ventricular wall thickness and connective tissue content were thought to be the dominating factors driving Phase 1 – Diastolic filling of the ventricle ventricular compliance; however, there is now evidence to suggest The first stage of the cardiac cycle is diastolic filling. As the that there are important contributing roles for many extracellular and ventricle relaxes, ventricular pressure decreases. When ventricular intracellular mechanisms. In fish hearts, it is likely that a combination pressure drops below atrial pressure, the atrioventricular valve opens of factors determine overall passive stiffness. and blood flows from the atrium into the ventricle. This phase of the The main components of the cardiac extracellular matrix (ECM) cardiac cycle is known as isovolumic relaxation, and it lasts from the are the interstitial fibrous proteins, collagen and elastin and time when the atrioventricular valves open until they close again. glycosaminoglycans, which connect to ECM proteins to form Ventricular pressure and, therefore, diastolic filling volume are proteoglycans (Cleutjens and Creemers, 2002; Fomovsky and largely determined by cardiac preload, which is determined by Holmes, 2010). The elastic elements of the ECM (collagen and venous pressure and atrial systole. The sinus venosus and atrium are elastin) provide structure and support to the chamber walls and are, larger than the ventricle and act as reservoirs by modulating the therefore, central to the overall passive tension of the ventricle volume of blood entering the heart (Farrell, 1991). To maintain (Katz, 2006). Matrix proteins also surround individual myocytes, correct diastolic function, the ventricle must be compliant enough to muscle bundles and blood vessels, forming a complex structural allow sufficient filling, but also needs to be strong enough to network of interstitial matrix and basement membrane (Sanchez- withstand the haemodynamic stress of pumping a large volume of Quintana et al., 1995). Together, this network of proteins helps to blood. Passive tension describes the resistance of a cardiac chamber maintain the structural integrity of the heart while also enabling – to diastolic filling and, therefore, plays a role in the Frank–Starling and controlling – the distensibility (i.e. the fold change in cardiac response of the heart (Shiels and White, 2008), where an increase in compliance) of the tissue. end-diastolic volume results in an increase in systolic contraction Collagen is the most common structural protein in the ECM and stroke volume. In rainbow trout, passive stiffness of the whole (Fomovsky and Holmes, 2010). It forms stiff fibres that support and ventricle increases following cold acclimation, as shown by maintain the alignment of myocytes by bearing wall stress. At high generating ex vivo pressure–volume relationships (Fig. 3) (Keen chamber volumes, the collagen fibres become stiff and straight to et al., 2016). Functionally, these decreases in chamber compliance resist overexpansion and damage to myocytes (Fomovsky and (see Glossary) may be cardioprotective, by providing support to the Holmes, 2010). In mammals, chronic increases in cardiac load are cardiac wall to counteract the increased haemodynamic stress often associated with increased myocardial collagen deposition, encountered during high cardiac load. However, excessive which allows the heart to resist the increased haemodynamic stiffening of the myocardium has been shown in mammals to stress. Collagen also increases the passive stiffness of the chamber reduce diastolic filling and, in severe cases, can lead to diastolic wall, so excessive fibrosis of the myocardium can reduce chamber dysfunction (Collier et al., 2012). It is currently unclear how compliance and chamber distensibility, which can have implications increased diastolic stiffness affects in vivo diastolic filling in fish. for diastolic filling (Collier et al., 2012). In the fish heart, collagen can These features are discussed in more detail below. be identified using PicroSirius Red staining, and it is visible in both the compact and spongy myocardium (Fig. 4A,B). In rainbow trout, Stiffness, compliance and the extracellular matrix myocardial fibrillar collagen content (Keen et al., 2016; Klaiman The end-diastolic pressure–volume relationship describes myocardial et al., 2011) and/or connective tissue content (Keen et al., 2016; relaxation. This relationship, and therefore cardiac compliance, is Klaiman et al., 2011) increases ∼1.7-fold and ∼3.5-fold, respectively, Pressure (kPa) Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 Rainbow trout Zebrafish Pericardial membrane Pericardial membrane A B Pericardial membrane Pericardial membrane Spongy myocardium Compact myocardium Compact myocardium Spongy myocardium Spongy myocardium Compact myocardium Compact myocardium Spongy myocardium Collagen content Thin/diffuse collagen Thick/dense collagen C D † † 0.4 Control Cold Control Cold 0.3 0.2 4 30 0.1 Control Cold Control Cold Compact myocardium Spongy myocardium Gene expression 2.0 a a EF 3.0 2.5 12 * 1.5 2.0 1.5 1.0 1.0 b 0.5 a c 0 0 0.5 Control Cold Control Cold 2.0 4 * 1.5 1.0 1.0 0.5 c 0 0 0.8 Control Cold Control Cold 2.0 2.5 0.6 b 2.0 1.5 0.4 b b 1.5 1.0 c 1.0 0.2 0.5 0.5 Control Cold Control Cold Fig. 4. Thermal remodelling of ventricular collagen in rainbow trout and zebrafish. Representative bright-field (left) and polarised-light (right) micrographs of control (A) rainbow trout and (B) zebrafish ventricular tissue sections stained with PicroSirius Red, which allows semi-quantification of fibrillar collagen content. Cold acclimation causes an increase in ventricular collagen content in (C) rainbow trout, but (D) a decrease in thick collagen fibres in the zebrafish ventricle. (E) Increased ventricular collagen content in rainbow trout is associated with increased mRNA expression of collagen-promoting genes (5°C; blue), compared with control (10°C; green), whereas warm acclimation (18°C; red) is associated with an increase in mRNA expression of collagen-degrading genes. (F) Following cold acclimation, zebrafish ventricles show an increase in mRNA expression of collagen-regulatory genes, suggesting increased collagen turnover. In the zebrafish experiment fish were maintained at 27°C (Control) or acclimated to 20°C (cold). All data are means±s.e. Letters and symbols indicate significant differences. Figures modified from Johnson et al. (2014) and Keen et al. (2016). Scale bars: 100 μm. Cold Control Warm Cold Control Warm Col1a1 Col1a2 Col1a3 TIMP2 MMP2 MMP9 MMP13 mRNA expression/β-actin Spongy collagen (%) Compact collagen (%) COL1A2/EF1α MMP13/EF1α MMP2/EF1α mRNA level mRNA level mRNA level Proportion of total Area (μm) collagen (%) TIMP2/EF1α MMP9/EF1α COL1A1/EF1α mRNA level mRNA level mRNA level Area (μm) Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 following cold acclimation (Fig. 4C), which is likely to protect the trout following thermal acclimation. Comparatively, in mammals, myocardium from the increased haemodynamic stress of pumping total cardiac connective tissue increases of ∼1.6-fold are considered cold viscous blood. However, the opposite response has been to be a pathological condition that stiffens the myocardium, which is observed in zebrafish, where there is significantly less thick collagen often associated with ∼1.3- to 2.1-fold increases in the ratio of type fibres in the hearts of fish acclimated to 20°C compared with those I:type III collagen – type I collagen is less extensible than type III acclimated to 28°C (Fig. 4D) (Johnson et al., 2014). One potential (Jalil et al., 1988, 1989; Marijianowski et al., 1995; Pauschinger explanation for these opposing responses is related to the difference in et al., 1999). Such changes are common, and permanent, in the blood pressure between zebrafish and trout. Adult zebrafish weigh hearts of patients suffering from cardiac hypertension, dilated between 0.3 and 1.0 g (Fuzzen et al., 2010) and measurements cardiomyopathy or chronic congestive heart failure, and they completed by Hu et al. (2001) indicate that peak ventricular pressure contribute to the associated diastolic dysfunction and eventual heart in these fish is 3 mmHg. Meanwhile, the blood pressure of ∼750 g failure (Jalil et al., 1988, 1989; Marijianowski et al., 1995; trout is approximately 50 mmHg (Clark and Rodnick, 1999). This Pauschinger et al., 1999). The ability of fish species, including suggests that there is less pressure to inflate the zebrafish heart. the zebrafish and trout, to regulate myocardial collagen content in Therefore, an increase in the stiffness of the zebrafish myocardium response to changes in physiological conditions suggests that fish caused by an acute decrease in temperature would make it more show greater cardiac phenotypic plasticity than mammals. difficult for the lacunae in the zebrafish heart to fill with blood during diastole. Further work is required to compare how cold acclimation Intracellular contribution to stiffness and compliance influences the passive stiffness of trout and zebrafish hearts. At the myocyte level, cardiac compliance during diastolic filling is However, recent work by Lee et al. (2016) using high-resolution influenced by a number of features. Firstly, the amount and speed of 2+ + 2+ echocardiography demonstrates that cold acclimation of zebrafish Ca removal from the cytoplasm by the SR and the Na /Ca does not alter the early peak velocity:atrial peak velocity (E/A) ratio exchanger alters stiffness and compliance through residual active 2+ (i.e. the ratio of early ventricular filling, where blood flows into the tension. The Ca affinity of troponin and the dissociation of 2+ ventricle solely due to pressure gradient, to ventricular filling aided by contractile proteins once Ca has dissociated from troponin (Katz, atrial contraction, which is the second phase of atrial filling), 2006) influences this relationship. Secondly, passive stiffness of the indicating that there was no loss of diastolic function. This study also cytoskeleton and of sarcomeric proteins such as titin plays a large role demonstrated that cold-acclimated fish had a slower isovolumetric in determining overall myocyte stiffness and compliance (Granzier contraction time compared with warm-acclimated fish when et al., 1996; Horowits et al., 1989; Shiels and White, 2008; Watanabe measured at 18°C (Lee et al., 2016). This suggests that cold- et al., 2002). Titin is a giant sarcomeric protein that runs from the acclimated fish show improved ejection, and that the zebrafish is able Z-line through to the M-line (Helmes et al., 1996; Linke, 2008; Linke to effectively compensate for the influence of low temperature on et al., 1996; Peng et al., 2007; Wu et al., 2000). Two titin isoforms cardiac function following cold acclimation. exist in the vertebrate adult heart: a shorter and stiffer N2B isoform Myocardial collagen content reflects a balance between collagen and a longer and more compliant N2BA isoform (Cazorla et al., 2000; deposition and degradation. Collagen degradation is regulated by Patrick et al., 2010). The ratio of the two isoforms modulates titin- matrix metalloproteinase (MMPs), and the gelatinase activity of based passive tension (Cazorla et al., 2000; Fukuda et al., 2005; MMPs is regulated by tissue inhibitors of MMPs (TIMPs). Linke, 2008; Trombitas et al., 2001). In addition, phosphorylation of Increased enzymatic activity of TIMPs inhibits collagen the N2B element by protein kinase A (PKA) or protein kinase G degradation by MMPs, and is associated with increased collagen (PKG) can decrease passive force (Krüger and Linke, 2009). Cardiac deposition. With cold-induced ventricular hypertrophy and fibrosis output in the rainbow trout heart can be modulated by up to 3-fold in rainbow trout, myocardial expression of MMP2 and MMP13 increases in stroke volume. Therefore, it is perhaps unsurprising that mRNA is downregulated (Keen et al., 2016), and there is an rainbow trout ventricular myocytes have a higher ratio of the associated upregulation of TIMP2 mRNA transcripts (Fig. 4E) compliant N2BA isoform to the stiffer N2B isoform compared with a (Keen et al., 2016). Conversely, cold acclimation of zebrafish – rat myocyte (Patrick et al., 2010). However, passive tension remains which causes a decrease in collagen content and in the proportion of higher in a fish myocyte than a rat myocyte due to a lower level of titin thick collagen fibres in the compact myocardium – is associated phosphorylation, which may explain the large Frank–Starling with an increase in the level of gene transcripts for MMP2 and response in fish hearts (Patrick et al., 2010). MMP9 in the heart (Fig. 4F) (Johnson et al., 2014). This suggests At present, the effect of temperature acclimation on the that there is an increase in collagen turnover that would result in the intracellular structure and titin remodelling in the fish heart is not observed changes in collagen content (Johnson et al., 2014), and is known. In mammals, the expression of specific titin isoforms shows further evidence that MMPs play a role in regulating collagen plasticity, with the changing haemodynamics that occur during content in the fish heart during thermal acclimation. cardiac growth altering titin ratios, but little is known about the The predominant fibrillar collagen in cardiac tissue is collagen I, mechanism (Linke, 2008). The ratios of titin isoforms have been followed by collagen III (Eghbali and Weber, 1990). Fibrillar suggested to shift to compensate for cardiac fibrosis by increasing collagen molecules are made by super-coiling three alpha amino the expression of the compliant N2BA isoform (Neagoe et al., acid chains into an α-helix. In mammals, collagen I is composed of 2002). However, increased compliance of titin may reduce systolic two type 1 (α1) and one type 2 (α2) subunits. However, in collagen I function via the Frank–Starling mechanism because of reduced titin of bony fishes, one of the α1 chains is replaced with a type 3 (α3) spring activity (Linke, 2008). In fish, the titin isoform ratio is also subunit (Saito et al., 2001). Keen et al. (2016) showed this fish- likely to be an important feature for determining the passive specific α3 chain is upregulated 1.4-fold with the cold-induced properties of the fish heart. Keen et al. (2016) demonstrated this in fibrosis observed in the trout heart. Interestingly, the α3 chain rainbow trout by measuring micromechanical stiffness of reduces the denaturation temperature of the collagen I molecule and ventricular tissue sections with atomic force microscopy. Cold makes it more susceptible to degradation by MMP13 (Saito et al., acclimation increased micromechanical stiffness by ∼1.9-fold (to 2001), which may explain the transient nature of cardiac fibrosis in ∼0.85 MPa), which is comparable to the stiffness recorded in Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 scarred mammalian myocardium following myocardial infarction until an SL of 2.6 μm. Since the trout heart has a high ejection (∼0.8 MPa) (Hiesinger et al., 2012). Furthermore, cumulative fraction volume (>80%; Franklin and Davie, 1992), this would allow frequency curves showed an even distribution of tissue stiffness, the ventricle to be stretched to a greater extent, and as a result, allow suggesting that tissue stiffness was increasing evenly across the for greater diastolic filling and increased strength of contraction. tissue rather than due to specific increases in the stiffness of the These factors are critical to the regulation of cardiac output via the structural components of the tissue, such as fibrillar collagen. Future Frank–Starling mechanism in fish (Shiels et al., 2006a). studies should aim to understand the changes in the intracellular structure of the fish myocyte that occur with temperature Myofibril remodelling acclimation and how these contribute to the overall changes in Force is produced in striated muscle by the cycling of cross-bridges passive tension of the fish ventricle. between the actin thin filaments and myosin thick filaments. This 2+ reaction, initiated by Ca binding to the thin filament, results in Cardiac hypertrophy muscle contraction. One mechanism for regulating contractile In mammals, wall thickness is known to affect passive stiffness of function in skeletal or cardiac muscle in the face of an the ventricle, therefore hypertrophy (muscle growth) or atrophy environmental stressor is to express an isoform of a protein that is (muscle loss) of the ventricle may influence the diastolic filling better suited for a particular physiological condition. For example, phase of the cardiac cycle. In the mammalian heart, hypertrophy is Crockford and Johnston (1990) demonstrated that cold acclimation of initiated by increased cardiac load caused by physiological carp resulted in the expression of a unique myosin light chain (MLC) stressors, including aerobic exercise and pregnancy, or a in skeletal muscle and also increased the expression of MLC-1 while pathological condition, such as a myocardial infarction or decreasing the expression of MLC-3. Previous work by Vornanen hypertension (Dorn, 2007; Dorn et al., 2003). The elevated (1994) has demonstrated that one isoform of MHC is expressed in the biomechanical strain of chronic pressure or volume overload skeletal muscle of carp in winter but that two isoforms are expressed in causes increased tension of the heart wall, which triggers the same muscle in summer. These changes in protein expression increased mRNA production and protein synthesis leading to correlate with altered myocyte contractility (Crockford and Johnston, cellular hypertrophy and increased connective tissue (Bishop, 1990; 1990; Vornanen, 1994). In the trout heart, cold acclimation has been Nadal-Ginard et al., 2003). Capillary growth is vital to provide the shown to alter the gene transcript levels for different isoforms of growing cardiac muscle with a sufficient supply of oxygen and cardiac myofilament proteins. More specifically, Genge et al. (2013) nutrition; thus, the secretion of angiogenic factors, such as vascular identified transcripts for two isoforms of TnC in the trout heart that endothelial growth factor (VEGF) is also observed (Weber and are modulated by cold acclimation. Troponin C (TnC) is the 2+ Janicki, 1989). Ca -activated trigger that initiates myocyte contraction (Box 1), A number of studies have shown increased ventricular mass and previous studies have demonstrated that manipulation of the (relative to body mass) in fish following cold acclimation (Aho and isoform working in the muscle can alter contractile function (Gillis Vornanen, 1998; Driedzic et al., 1996; Farrell et al., 1988; Kent et al., 2005). In addition, Alderman et al. (2012) demonstrated that the et al., 1988; Klaiman et al., 2011; Vornanen et al., 2005). The trout heart expresses the gene transcripts for seven different TnI increased ventricular mass is mainly attributed to an increase in isoforms, and that the abundance of four of these changes with cold myocyte size, suggesting it is a physiological hypertrophic acclimation. There are considerable differences within the sequences response, in the spongy layer (Aho and Vornanen, 1998; Driedzic of the seven TnI isoforms found in trout heart (Alderman et al., 2012), et al., 1996; Keen et al., 2016; Klaiman et al., 2011; Vornanen et al., which likely result in differences in the functional properties of the 2005). However, some studies suggest that myocyte hyperplasia protein. If the changes in TnI transcript abundance translate into (increase in cell numbers) accounts for around 20% of myocardial changes in the complement of protein isoforms present in the muscle, 2+ growth, in addition to hypertrophy (Farrell et al., 1988; Keen et al., this would potentially alter the Ca sensitivity or the kinetics of 2016; Sun et al., 2009). The mRNA expression of VEGF is contraction. Such a strategy may be utilized to maintain contractile upregulated during cold acclimation, suggesting an increased blood function in the trout heart with cold acclimation. supply to the compact layer (Jørgensen et al., 2014; Keen et al., Phosphorylation of key regulatory proteins – including cardiac 2016). This hypertrophic response upon cold acclimation, along troponin I (cTnI), cardiac troponin T (cTnT) and myosin binding with the increase in cardiac connective tissue, indicates that changes protein C (MyBP-C) – can modulate myofilament function in the in physiological conditions can elicit a significant phenotypic vertebrate heart (reviewed by Shaffer and Gillis, 2010). In the response as the heart continues to function. mammalian heart, these proteins can be targeted by protein kinase A (PKA) or protein kinase C (PKC) following β-adrenergic or Phase 2 – Pressure generation α-adrenergic stimulation, respectively (Shaffer and Gillis, 2010). The second stage of the cardiac cycle is pressure generation. The resultant functional changes that follow PKA phosphorylation 2+ Following ventricle filling, the ventricular myocardium starts to in the mammalian heart include a decrease in the Ca sensitivity of 2+ contract isometrically, building up pressure within the ventricle, force generation, increased kinetics of Ca activation and a which closes the atrioventricular valve. An increase in end-diastolic decrease in force generation (Chandra et al., 1997; Dong et al., volume results in an increase in systolic contraction and stroke 2007). Using a chemically skinned myofilament preparation from volume (Frank–Starling response). At the cellular level, an increase trout hearts, it has been shown that PKA phosphorylation decreases in pressure during ventricle loading stretches the myocytes in the cross-bridge cycling and maximal force generation (Gillis and ventricle, increasing sarcomere length (SL) and, thus, changing the Klaiman, 2011). Interestingly, cold acclimation of trout results in an force of contraction (reviewed in Shiels and White, 2008). increase in the maximal rate of the cardiac actomyosin-ATPase Mammalian cardiac myocytes show an increase in the force of activity (Klaiman et al., 2014; Yang et al., 2000) (Fig. 5A), an 2+ contraction with an increase in SL until a peak of ∼2.2 μm (Gordon increase in the Ca sensitivity of force generation by skinned et al., 1966); however, Shiels et al. (2006a) have demonstrated that ventricular trabeculae (see Glossary; Klaiman et al., 2014) (Fig. 5B) the active force of contraction in trout cardiac myocytes increases as well as an increase in the magnitude and rate of pressure Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 Fig. 5. Cardiac contractile properties A 4°C of trout acclimated to 4°C, 11°C and 11°C 17°C 17°C. (A) The maximal activity of 2+ actomyosin Mg -ATPase isolated from ventricles is higher in preparations from cold-acclimated trout than those from warm-acclimated trout when measured 2+ at 17°C. (B) The Ca sensitivity of force generation by cardiac trabeculae from trout acclimated to 4°C (blue line) is greater than that of trabeculae from trout acclimated to 11°C (black line) or 17°C (red line) when measured at 15°C. 20 pCa is the pCa at half-maximum force. SL, sarcomere length. (C) Developed pressures at ventricle volumes greater 17°C, pH=7 than baseline are higher for the 4°C acclimated (blue symbols) fish than 8.0 7.5 7.0 6.5 6.0 5.5 5.0 those for the 11°C (black symbols) and pCa 17°C (red symbols) acclimated fish. Circles indicate ventricular developed pressures, while squares indicate pCa diastolic pressures. All data are means± 1.0 4°C 5.69±0.03 s.e. Figures modified from Klaiman et al. 11°C 5.61±0.01 (2011) and Klaiman et al. (2014). The 17°C 5.59±0.02 images on the right of the panels are: (A) 0.8 a schematic of a thick and thin filament inside a cardiac myofilament; (B) a micrograph of a trout cardiac 0.6 myofilament preparation attached to a force transducer and servo motor via aluminium clips; and (C) a schematic of 0.4 a trout heart. 0.2 15°C, pH=7, SL=2.2 μm 6.2 6.0 5.8 5.6 5.4 5.2 pCa 010 20 30 40 50 60 Balloon volume (μl) generation by the isolated heart (Fig. 5C) (Klaiman et al., 2014). are due, at least in part, to post-translational changes in the This indicates that the heart functions better with cold acclimation myofilament regulatory proteins (Klaiman et al., 2011, 2014). (Klaiman et al., 2014). Quantification of phosphorylation of the myofilament proteins in the cold-acclimated hearts demonstrates a Cardiac morphology decrease in the phosphorylation of cTnT, slow skeletal TnT and Cardiac hypertrophy following cold acclimation in fish is a MyBP-C. This suggests that the changes in myofilament function strategy to help compensate for the effect of low temperature on 2+ Actomyosin Mg -ATPase activity –1 –1 Ventricular pressure (mmHg) Normalized force generation (nmol Pi min mg ) Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 Spongy myocardium Compact myocardium Com 1,2,3 1,2,3 M Myocyte bundle hypertrophy Compact thickness C 1,3 1,2,3 Extra-bundular sinus E Fibrillar and amorphous collagen F mRNA m of muscle growth genes Whole chamber passive stif W fness 3 3 mRNA m of hypertrophic markers Micromechanical stif M fness of tissue mRNA m of collagen-promoting genes 5 Cellular lipid droplets C mRNA m of collagen-degrading Cellular glycogen C 17–18°C genes g 1,2,3 Amorphous collagen A Whole chamber passive W stif s fness Cellular lipid droplets C Cellular glycogen Blood to ventral aorta Bulbus arteriosus Ventricle (compact myocardium) Atrium 10–11°C Ventricle (spongy myocardium) Sinus venosus Venous blood from cardinal and hepatic veins 1,2,3 Myocyte bundle hypertrophy M 1,2,3 Compact thickness C 1,3 Extra-bundular sinus Ex Fibrillar and amorphous collagen F 3,4 mRNA m of muscle growth genes 3 Whole chamber passive stif W fness 4–5°C mRNA m of hypertrophic markers 3 T Tissue micromechanical stiffness mRNA m of collagen-promoting genes 5 Cellular lipid droplets C mRNA m of collagen-degrading genes Cellular glycogen 1,2,3 Amorphous collagen A Whole chamber passive stif W fness T Tiissue micromechanical stiffness Cellular lipid droplets C Cellular glycogen Fig. 6. Thermal remodelling of the rainbow trout heart. A summary of the effects of chronic cooling (5°C) and chronic warming (18°C) on the rainbow trout 1 2 3 4 heart, compared with those of fish kept at control temperature (10°C). Klaiman et al., 2011; Klaiman et al., 2014; Keen et al., 2016; Vornanen et al., 2005; 5 6 Driedzic et al., 1996; Driedzic and Gesser, 1994. the active properties of the muscle by increasing muscle mass, above). In this study, there were also changes to the morphology thus increasing the pressure-generating ability of the myocardium of the heart (Klaiman et al., 2014), including a decrease in the (Driedzic et al., 1996; Gamperl and Farrell, 2004; Graham and relative proportion of compact myocardium and a reciprocal Farrell, 1989; Keen et al., 2016; Klaiman et al., 2011). However, increase in spongy myocardium (Fig. 6 and Table 1). Such a recent work by Klaiman et al. (2014) demonstrated that cold change in cardiac morphology with cold acclimation has been acclimation of trout can increase the pressure-generating capacity reported in other studies of trout (Farrell et al., 1988; Keen et al., of the heart in the absence of a hypertrophic response (Fig. 5C). 2016; Klaiman et al., 2011), as well as for zebrafish (Johnson This change in function is likely to be due, at least in part, to et al., 2014). In the fish heart, the spongy myocardium is alterations of the myofilaments (see ‘Myofibril remodelling’ composed of trabecular sheets that enable the formation of Journal of Experimental Biology A A U U U T T T C C G G G A A A G G G A A C C T T C C REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 Table 1. Integrated remodelling response of the rainbow trout ventricle following prolonged cold exposure, across multiple levels of biological organization Response References Gene expression Anti-sense strand Anti-sense strand Vornanen et al., 2005; Keen et al., 2016 ↑ mRNA of muscle growth genes ↑ mRNA of hypertrophic markers Keen et al., 2016 mRNA mRNA ↑ mRNA of collagen promoting genes Keen et al., 2016 ↓ mRNA of collagen degrading genes Keen et al., 2016 G G G G ↑ VEGF expression Keen et al., 2016 C C Sense strand Senses estrand Myofilaments Tnc Tm ↑ AM-ATPase Yang et al., 2000; Klaiman et al., 2011 Tnl Actin TnT ↑↓ Gene expression of 4 TnI isoforms and 2 Alderman et al., 2012; Genge et al., 2013 cTnC isoforms ↓ Phosphorylation of TnT Klaiman et al., 2014 Myosin S1 cMyBP-C C0 C1 Myosin S2 C2 C3 C4 C5 C6 C7 C8 C9 C10 ELC Titin LMM RLC Calcium handling 2+ RyR Keen et al., 1994; Aho and Vornanen, 1998, 1999 ↑ Rate of SR Ca release/uptake 2+ SERCA Ca PLB ↑ SERCA transcript expression Korajoki and Vornanen, 2012 NCX ↑ β-adrenergic receptor density and sensitivity Graham and Farrell, 1989; Keen et al., 1993; Aho 3 Na SR and Vornanen, 2001 ∼ RyR density and localization Birkedal et al., 2009 2+ DHPR Ca MF 2+ Ca NCX 2+ SL Ca ATPase 3 Na Myocyte Aho and Vornanen, 1999 ↑ Rate of contraction (intact muscle) ↓ Refractoriness Aho and Vornanen, 1999 2+ ↑ Ca sensitivity of skinned trabeculae Klaiman et al., 2014 Whole heart ↑ Heart size Farrell et al., 1988; Graham and Farrell, 1989; Atrium Sinus Vornanen et al., 2005; Birkendal et al., 2009; venosus Klaiman et al., 2011; Keen et al., 2016a Bulbus ↑ Connective tissue content Klaiman et al., 2014 arteriosus ↑ Fibrillar collagen content Keen et al., 2016 ↓ Compact layer thickness Farrell et al., 1988; Klaiman et al., 2014 ↑ Heart rate Aho and Vornanen, 2001 ↑ Passive stiffness Keen et al., 2016 ↑ Magnitude and rate of developed pressure Klaiman et al., 2014 Ventricle + 2+ Tm, tropomyosin; LMM, light meromyosin; RLC, regulatory light chain; ELC, essential light chain. NCX, Na /Ca exchanger; RyR, ryanodine receptor; SERCA, 2+ sarcoplasmic endoplasmic reticulum Ca -ATPase; PLB, phospholamban; DHPR, dyhydropyridine receptor. On all panels an upwards arrow indicates an increase, a downwards arrow indicates a decrease and the two arrows together indicate a change; ∼ indicates no response. G G C C C C C C G G G U U A A A Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 lacunae that fill with blood during diastole. Then, during systole, preload, and therefore ejection fraction, is primarily determined by the ventricular trabeculae act as ‘contractile girders’, helping to late diastolic filling, which is dependent on atrial contraction (Farrell pull the compact myocardium inwards during contraction and Jones, 1992; Lee et al., 2016). (Pieperhoff et al., 2009). Additionally, the small lacunae that are formed by the trabecular nature of the spongy muscle lower Influence of warm acclimation on the structure and function the wall tension against which the myocytes have to work, i.e. of the heart the trabeculae reduce the cardiac work load as explained by When the temperature of ventricular trabeculae from Atlantic cod LaPlace’s law. This functional organization of the myocardium is was increased from 10 to 20°C, the amount of work required to thought to enable the extremely high ejection fraction of the trout lengthen the preparations nearly doubled (Syme et al., 2013). The heart (∼80%) compared with that of the mammalian heart (50– authors suggest that this was due to an increase in the resting tension 60%), which does not contain spongy myocardium (Franklin and of the muscle (Syme et al., 2013). Such a response could be caused 2+ Davie, 1992). The observed increase in spongy myocardium seen by the increase in temperature enhancing the Ca sensitivity of the in the trout heart with cold acclimation would, therefore, increase myofilament, thereby increasing the number of active cross-bridges the stroke volume of the heart while also increasing the relative during diastole (Gillis et al., 2005, 2000, 2003b; Gillis and Tibbits, proportion of contractile machinery. Such a change would make 2002). This effect would stiffen the muscle, impair cardiac filling the heart able to pump more blood per contraction. and potentially limit the ability of the fish to maintain stroke volume as temperature rises (Syme et al., 2013). Therefore, just as the Length-dependent changes in force generation structure and function of the fish heart may remodel to (partially) Changes in the resting length of the sarcomere can affect the compensate for a decrease in ambient temperature, it may also strength of contraction and, thus, the pressure-generating capacity remodel to offset the effects of increased environmental of the ventricle. Interestingly, Klaiman et al. (2014) demonstrated temperatures. For wild fish, increases in ambient temperature may that the difference in developed pressure at higher ventricle be more complex than the decreases associated with winter cold, as volumes between hearts from cold- and warm-acclimated fish was flow, shade and water depth can all affect water temperature. As greater than at smaller ventricle volumes. One possible such, behavioural thermoregulation is likely to play a key role in explanation for this result is that the cardiac muscle of fish that keeping fish cool. However, as overall ambient temperature have been acclimated to high or low temperatures may respond increases with global climate change, ectothermic animals living differently to stretch. As discussed above, rainbow trout cardiac in temperate environments are likely to experience larger muscle has a larger working range of the Frank–Starling curve temperature fluctuations, including periods of higher than average compared with that of rats, as well as a longer optimal sarcomere temperatures during summer months. The ability of fish species to length (2.6 µm versus 2.2 µm) (Patrick, et al., 2010; Shiels et al., respond to acute and prolonged changes in temperature may 2006a; Cazorla et al., 2000). In addition, previous work in therefore be essential for their long-term survival. mammals has shown that following a physiological stressor such Although laboratory-based temperature acclimation studies do not as exercise training, cardiac tissue has a greater response to stretch capture the complexity of temperatures that fish may encounter in (known as length-dependent activation) (Diffee and Nagle, 2003). open water, they offer an insight into the physiological remodelling Thus, it is possible that length-dependent activation is more that may occur. For example Badr et al. (2016) demonstrated that prominent in the trout heart following acclimation to cold warm acclimation increases the temperature at which heart rate temperatures. This hypothesis deserves future investigation. becomes irregular in the roach Rutilus rutilus. In addition, Klaiman et al. (2014) demonstrated that there is a decrease in the magnitude Phase 3 – Ejection and rate of ventricular pressure generation in hearts from warm- The third stage of the cardiac cycle is ejection. Following pressure acclimated trout compared with control (11°C) and cold-acclimated generation by the myocardium, the bulbo-ventricular valve opens, (4°C) fish when measured at a common experimental temperature and blood is forced from the ventricle into the bulbus arteriosus (Figs 5 and 6). Our groups have also demonstrated that warm in the fish outflow tract and from there to the rest of the body. In acclimation causes a reduction in overall ventricular mass, an increase zebrafish, ejection time decreases with acute reductions in ambient in the thickness of the compact layer, and a decrease in connective temperature; however, there are no effects following cold tissue content (Klaiman et al., 2011; Keen et al., 2016). The acclimation (Lee et al., 2016). Heart rate determines the duration decreased ventricular mass is attributed to a reduction in the area of between ejections. Although an acute decrease in temperature slows the spongy myocardium; therefore, morphologically, the ventricle heart rate (Driedzic and Gesser, 1994), cold acclimation results in shows the direct opposite response to that observed following cold partial thermal compensation (Aho and Vornanen, 1999; Little and acclimation. The increase in compact layer thickness and decrease Seebacher, 2014). The end result may increase isometric force in spongy layer thickness are linked to a functional increase in generation and thus ejection of blood from the ventricle. ventricular compliance (Keen et al., 2016), suggesting that the Conversely, stroke volume is not altered by acute temperature volume of blood being pumped per beat is reduced. As an increase in change (Clark et al., 2008; Gollock et al., 2006; Lee et al., 2016; physiological temperature increases heart rate in fish (Aho and Mendonca et al., 2007; Steinhausen et al., 2008), whereas during Vornanen, 2001; Badr et al., 2016; Lee et al., 2016), this suggests that chronic cooling it may remain constant or increase. Although Lee the heart is pumping less blood per beat at a faster rate. What is et al. (2016) showed that stroke volume peaks when ambient currently unknown, however, is whether and how the trout heart can temperature matches acclimation temperature, cold acclimation remodel to temperatures above its normal seasonal range, and what significantly increases systolic function, with increases in ejection the functional consequence of such remodelling is. fraction and fractional shortening, which is consistent with increases It is interesting to note that the cold-induced increase in collagen in the expression of contractile proteins (as explained above) (Genge deposition documented in the trout heart is reversed following et al., 2013). In zebrafish, acute temperature change does not affect chronic warming (Klaiman et al., 2011; Keen et al., 2016). In the E/A ratio, suggesting that – at all temperatures – ventricular contrast, in mammals collagen deposition can become relatively Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 Bailey, J. R. and Driedzic, W. R. (1990). Enhanced maximum frequency and force fixed and is often the substrate for cardiac pathologies (arrhythmias, development of fish hearts following temperature acclimation. J. Exp. Biol. 149, diastolic dysfunction) in mammals (e.g. Nattel et al., 2008). Indeed, 239-254. in mammalian hearts, removing or reversing the trigger for Ballesta, S., Hanson, L. M. and Farrell, A. P. (2012). The effect of adrenaline on the temperature dependency of cardiac action potentials in pink salmon remodelling does not necessarily result in a reversion to the Oncorhynchus gorbuscha. J. Fish Biol. 80, 876-885. original state. The plasticity of the remodelling responses to Birkedal, R., Christopher, J., Thistlethwaite, A. and Shiels, H. A. (2009). warming and cooling is obviously well suited to a mesothermic Temperature acclimation has no effect on ryanodine receptor expression or fish such as the trout, but the mechanisms that permit these often subcellular localization in rainbow trout heart. J. Comp. Physiol. B 179, 961-969. Bishop, S. P. (1990). The myocardial cell: normal growth, cardiac hypertrophy and opposite responses are only just beginning to be examined. response to injury. Toxicol. Pathol. 18, 438-453. Blumenschein, T. M. A., Gillis, T. E., Tibbits, G. F. and Sykes, B. D. (2004). Effect Conclusions of temperature on the structure of trout troponin C. Biochemistry 43, 4955-4963. Boustany, A. M., Matteson, R., Castleton, M., Farwell, C. and Block, B. A. (2010). The ability of some fish to remodel their heart in response to Movements of pacific bluefin tuna (Thunnus orientalis) in the Eastern North Pacific changes in environmental temperature has ecological consequences, revealed with archival tags. Prog. Oceanogr. 86, 94-104. as it enables them to remain active over a wide range of Cazorla, O., Freiburg, A., Helmes, M., Centner, T., McNabb, M., Wu, Y., environmental temperatures. Such plasticity may also improve Trombitas, K., Labeit, S. and Granzier, H. (2000). Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ. Res. 86, 59-67. their ability to maintain cardiac function as average seasonal Chandra, M., Dong, W.-J., Pan, B.-S., Cheung, H. C. and Solaro, R. J. (1997). temperatures increase with global climate change. Independent of Effects of protein kinase A phosphorylation on signaling between cardiac troponin these potential advantages, the ability of fish to remodel their heart I and the N-terminal domain of cardiac troponin C. Biochemistry 36, 13305-13311. Churcott, C. S., Moyes, C. D., Bressler, B. H., Baldwin, K. M. and Tibbits, G. F. in response to changes in environmental conditions is a significant 2+ (1994). Temperature and pH effects on Ca sensitivity of cardiac myofibrils: a feat that results from significant phenotypic plasticity. Current and comparison of trout with mammals. Am. J. Physiol. 267, R62-R70. future studies should investigate how rapidly a fish heart can Clark, R. J. and Rodnick, K. J. (1999). Pressure and volume overloads are associated with ventricular hypertrophy in male rainbow trout. Am. J. Physiol. 277, remodel in response to a change in environmental temperature and R938-R946. examine the physiological consequences of multiple remodelling Clark, T. D., Taylor, B. D., Seymour, R. S., Ellis, D., Buchanan, J., Fitzgibbon, events. In addition, all known studies have looked at fixed time Q. P. and Frappell, P. B. (2008). Moving with the beat: heart rate and visceral points (6 or 8 weeks) of thermal acclimation and not at the time temperature of free-swimming and feeding bluefin tuna. Proc. R. Soc. B Biol. Sci. 275, 2841-2850. course of remodelling. Such information would be relevant to Cleutjens, J. P. M. and Creemers, E. E. J. M. (2002). Integration of concepts: understanding how stochastic environmental temperatures may cardiac extracellular matrix remodeling after myocardial infarction. J. Card. Fail. 8, affect natural fish populations. Such knowledge also has significant S344-S348. Collier, P., Watson, C. J., van Es, M. H., Phelan, D., McGorrian, C., Tolan, M., biomedical application by increasing our understanding of what Ledwidge, M. T., McDonald, K. M. and Baugh, J. A. (2012). Getting to the heart limits the ability of the vertebrate heart to remodel in response to a of cardiac remodeling; how collagen subtypes may contribute to phenotype. physiological stressor and providing novel insights useful for the J. Mol. Cell. Cardiol. 52, 148-153. development of strategies to control pathological remodelling seen Cortemeglia, C. and Beitinger, T. L. (2005). Temperature tolerances of wild-type and red transgenic zebra Danios. Trans. Am. Fish. Soc. 134, 1431-1437. in mammalian hearts. Crockford, T. and Johnston, I. A. (1990). Temperature acclimation and the expression of contractile protein isoforms in the skeletal muscles of the common Acknowledgements carp (Cyprinus carpio L.). J. Comp. Physiol. 160, 23-30. The authors thank Dr S. A. Alderman for editorial comments on an earlier version of Diffee, G. M. and Nagle, D. F. (2003). Exercise training alters length dependence of the manuscript. contractile properties in rat myocardium. J. Appl. Physiol. 94, 1137-1144. Dong, W.-J., Jayasundar, J. J., An, J., Xing, J. and Cheung, H. C. (2007). Effects Competing interests of PKA phosphorylation of cardiac troponin I and strong crossbridge on The authors declare no competing or financial interests. conformational transitions of the N-domain of cardiac troponin C in regulated thin filaments. Biochemistry 46, 9752-9761. Dorn, G. W.II. (2007). The fuzzy logic of physiological cardiac hypertrophy. Funding Hypertension 49, 962-970. A.N.K. is supported by a Doctoral Training Partnership from the Biotechnology and Dorn, G. W., II, Robbins, J. and Sugden, P. H. (2003). Phenotyping hypertrophy: Biological Sciences Research Council (BBSRC). J.M.K. is supported by a Post eschew obfuscation. Circ. Res. 92, 1171-1175. Doctoral Fellowship from the Heart and Stroke Foundation of Canada. T.E.G. is Driedzic, W. R. and Gesser, H. (1994). 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Temperature-induced cardiac remodelling in fish

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© 2017. Published by The Company of Biologists Ltd | Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 REVIEW 1 2 1 3, Adam N. Keen , Jordan M. Klaiman , Holly A. Shiels and Todd E. Gillis * ABSTRACT the wild (Cortemeglia and Beitinger, 2005; Sidhu et al., 2014) and can experience a 10°C change in temperature between winter and Thermal acclimation causes the heart of some fish species to undergo summer (López-Olmeda and Sánchez-Vázquez, 2011). Marine significant remodelling. This includes changes in electrical activity, species, such as tunas, also experience temperature changes energy utilization and structural properties at the gross and molecular seasonally (from 11 to 24°C) associated with oceanic migrations, level of organization. The purpose of this Review is to summarize and acutely (>10°C change) when diving through the thermocline the current state of knowledge of temperature-induced structural (Boustany et al., 2010). Although a change in temperature will affect remodelling in the fish ventricle across different levels of biological the function of all organs, the function of the heart is especially organization, and to examine how such changes result in the important because of its role in moving oxygen, metabolic modification of the functional properties of the heart. The structural substrates and metabolic byproducts around the body, and remodelling responseisthought tobe responsible forchanges in cardiac 2+ therefore supporting active biological processes. Thus, many fish stiffness, the Ca sensitivity of force generation and the rate of force have mechanisms that preserve cardiac function across seasonal generation by the heart. Such changes to both active and passive temperature changes. properties help to compensate for the loss of cardiac function caused by The purpose of this Review is to examine temperature-induced a decrease in physiological temperature. Hence, temperature-induced structural remodelling of the ventricle in the hearts of selected fish cardiac remodelling is common in fish that remain active following species. We build upon excellent original work (i.e. Vornanen et al., seasonal decreases in temperature. This Review is organized around 2005) and comprehensive reviews of cardiac plasticity in fish (e.g. the ventricular phases of the cardiac cycle – specifically diastolic filling, Gamperl and Farrell, 2004). Importantly, here, we review changes in isovolumic pressure generation andejection – so that theconsequences both the active and passive properties (see Glossary) of the fish heart of remodelling can be fully described. We also compare the thermal following prolonged temperature change. We discuss ways in which acclimation-associated modifications of the fish ventricle with those the remodelling preserves or improves function (physiological seen in the mammalian ventricle in response to cardiac pathologies and remodelling) and ways in which the remodelling may relate to exercise. Finally, we consider how the plasticity of the fish heart may be dysfunction (pathological remodelling). Indeed, one of the interesting relevant to survival in a climate change context, where seasonal aspects of thermal remodelling in the fish heart is that it involves temperature changes could become more extreme and variable. changes that are similar to those observed during both physiological KEY WORDS: Cardiac function, Cardiac histology, Cardiac and pathological remodelling in mammalian hearts (see Dorn, 2007; remodelling, Connective tissue, Thermal acclimation Keen et al., 2016; Klaiman et al., 2011; Klaiman et al., 2014). We acknowledge that other aspects of fish heart function change with Introduction thermal acclimation, most notably the electrical properties. Pacemaker Ectothermic animals living in temperate environments can output can be reset, partly as a result of temperature-related changes in experience significant, long-term changes in ambient temperature. electrical excitability (Aho and Vornanen, 2001; Ekström et al., These seasonal fluctuations influence every level of biological 2016). Electrical excitability itself is modulated by temperature- function as a result of the universal effect of temperature on dependent shifts in ion channel densities and/or isoform switches molecular interactions. Consequently, biochemical, physiological which can vary between species and life histories (Vornanen, 2016; and biomechanical processes are all affected by changes in Badr et al., 2016). temperature. However, a number of ectothermic species, including In this Review, we focus on ventricular remodelling, primarily some fish, remain active across the seasons. These fish species in two species – rainbow trout and zebrafish. Cardiac remodelling include salmonids such as rainbow trout (Oncorhynchus mykiss), in the trout has been extensively studied and, as a cold-active which, depending on the strain, can remain active at temperatures species, its heart develops robust cardiac outputs (see Glossary) ranging from ∼4 to 24°C (Anttila et al., 2014; Elliott and Elliott, across a range of temperatures. We also discuss recent work on 2010; Rodnick et al., 2004). Members of the minnow family, such cardiac remodelling in the zebrafish – a species that has become as the zebrafish (Danio rerio), also have broad thermal tolerances in a popular model for understanding the development and regenerative capabilities of the vertebrate heart. With >30,000 extant species of fish (Nelson, 2006), the possible remodelling Division of Cardiovascular Science, School of Medicine, Faculty of Biology, phenotypes are abundant. We do not attempt to cover all of these in Medicine and Health, University of Manchester, Manchester, M13 9NT, UK. Department of Rehabilitation Medicine, University of Washington, Seattle, WA this Review, however, we include key studies on other fish species 98109, USA. Department of Integrative Biology, University of Guelph, Guelph, such as tunas, cod, flat fish and carp, where appropriate. A key aim Ontario, Canada N1G 2W1. of this Review is to show how thermal remodelling of active and *Author for correspondence ([email protected]) passive properties work together to preserve cardiac function across temperatures. For this reason, we have divided the Review T.E.G., 0000-0002-8585-0658 into three main sections, each addressing one of the ventricular This is an Open Access article distributed under the terms of the Creative Commons Attribution phases of the cardiac cycle: diastolic filling, isovolumic pressure License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, generation and ejection. Through this approach, we hope to distribution and reproduction in any medium provided that the original work is properly attributed. Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 this Review focuses on the force-generating capacity of the myocardium rather than cycle frequency. Changes in cardiac force Glossary Active properties of the heart are often the inverse of rate changes and compensate (at least partially) Properties that affect muscle contraction, including rate of cross-bridge for the direct effect of temperature in altering cycle frequency. Acute 2+ cycling and sensitivity to Ca . cooling also increases blood viscosity, which directly affects Bradycardia vascular resistance and increases cardiac load (Graham and Farrell, A reduction in the rate of cardiac contraction. 1989; Graham and Fletcher, 1985). Although these effects of acute Cardiac contractility 2+ temperature are detrimental to contractile function, chronic exposure Ability of heart to contract and generate force when stimulated by Ca . Cardiac myofilaments results in compensatory changes that limit their consequences for Primarily composed of the actin thin filament and myosin thick filament cardiac output, as discussed later in this Review. and responsible for force generation in striated muscle. Cardiac output Acute effects on the myofilaments Blood volume pumped by the heart per unit time, calculated as the An acute decrease in the temperature of the vertebrate heart, product of contraction Hz and stroke volume. including those from mammals and fish, impairs contractile Cardiac stiffness Ability of the heart to resist stretching, determined by both the active and function, as the thin filaments in cardiac muscle have a reduced 2+ passive properties of the muscle. Inverse of compliance. sensitivity to Ca at lower temperatures, resulting in a loss of force- Cardioplegic generating capacity (Churcott et al., 1994; Harrison and Bers, 1990; Reduction in cardiac contractility. Stephenson and Williams, 1985). See Box 1 for an explanation of Chamber compliance 2+ the Ca -mediated activation of cardiac contraction. The cold- Inverse of stiffness, can be measured as the change in pressure for a 2+ associated decrease in Ca sensitivity in cardiac muscle has been given change in volume. reported in a variety of animals, including trout, frogs, mice, rats, Inotropic effects Affecting the force of contraction. rabbits, ferrets and ground squirrels (Churcott et al., 1994; Harrison Passive properties of the heart and Bers, 1989; Liu et al., 1993, 1990). Studies by Gillis et al. Non-contractile properties that affect the stiffness of the heart and (Gillis et al., 2005, 2000, 2003b; Gillis and Tibbits, 2002) show that influence the ability of the heart to relax and fill with blood between 2+ this decrease in Ca sensitivity following an acute reduction in heartbeats. This is affected by collagen composition and the sarcomere 2+ temperature is due to a decrease in the Ca affinity of cardiac protein titin. 2+ troponin C, which is the Ca -activated trigger for the muscle (see Q effects The change in rate of biochemical reaction that occurs with a 10°C Box 1). Although the cardiac muscle of trout and mammals behaves change in temperature. in a similar way in response to reduced temperatures, trout Ventricular trabeculae myofilaments (see Glossary) have several characteristics that Discretebundles or sheetsof musclewithin thespongy myocardiumoffish. 2+ illustrate the integrated and comprehensive nature of the thermal Box 1. Ca -mediated activation of the heart 2+ cardiac remodelling response. Ca is responsible for initiating and regulating the contraction of striated muscle. Following the firing of the sinoatrial node, also known as the For simplicity, we have structured the Review around cardiac pacemaker, cellular membranes of cardiac myocytes in the heart observations associated with cold acclimation. Historically, 2+ are depolarized, which causes the L-type Ca channels to open. As a responses to cold acclimation have been the main experimental 2+ result, Ca enters the cell and can interact directly with the interest (Bailey and Driedzic, 1990; Driedzic et al., 1996; Farrell, 2+ myofilaments. Ca influx can also activate the ryanodine receptors 1991; Haverinen and Vornanen, 2007; Keen et al., 1993, 1994; (RyRs) located in the membrane of the sarcoplasmic reticulum (SR). 2+ Lurman et al., 2012); however, with rising temperatures becoming a The SR is an organelle that stores and releases Ca in the myocyte. The 2+ activation of the RyRs causes the release of Ca from the SR into the global concern, there is increasing interest in the effect of warming 2+ 2+ cytosol in a process called Ca -initiated Ca release (CICR). CICR is (Farrell et al., 1996; Farrell, 2002; Keen et al., 2016; Klaiman et al., vital for the contraction of mammalian hearts but less so for fish hearts, 2011; Syme et al., 2013). Therefore, we have added a concluding 2+ 2+ as extracellular Ca influx delivers sufficient Ca to the myofilaments in section to discuss the specific implications of prolonged warm most fish species (see Shiels and Galli, 2014). The increase in cytosolic temperatures on fish heart function. 2+ 2+ Ca activates the actin thin filament when Ca binds to the troponin (Tn) 2+ complex through cardiac troponin C (cTnC). Ca binds to a binding site Acute temperature change and cardiac function in the N-terminus of the protein, which initiates a conformational change in the molecule that triggers a series of further conformational changes Acute effects on whole heart function through the other component proteins of the thin filament, leading to the Acute temperature change (minutes to hours) directly influences exposure of a myosin-binding site on the surface of actin (see Gillis and physiological processes in fish through Q effects (see Glossary) on Tibbits, 2002). As a result, a myosin head binds to the actin thin filament, reaction rates. As the temperature drops, the heart becomes resulting in the formation of a cross-bridge. The cross-bridge generates bradycardic (see Glossary; Keen et al., 1993), which is largely due force with the hydrolysis of ATP, and the myosin head flexes. The to a greater diastolic duration, with systolic duration less affected formation of force-generating cross-bridges along the contractile element leads to the shortening of the sarcomere and the contraction of the (Badr et al., 2016). The greater diastolic duration acts to maintain muscle during systole. As a result, blood is pumped out of the heart. cardiac output by increasing filling time, which can lead to an increase 2+ For the heart to relax, Ca is pumped back into the SR through the SR in stroke volume even though cardiac contractility (see Glossary), 2+ + 2+ Ca -ATPase or out of the cell through the Na /Ca exchanger, causing force production and cycle frequency are reduced at lower 2+ 2+ cytosolic Ca concentrations to decrease. This causes Ca to temperatures (Shiels et al., 2002; Vornanen et al., 2005). Changes disassociate from the actin thin filament, resulting in the inhibition of in cycle frequency (i.e. heart rate; as reviewed by Vornanen, 2016) further cross-bridge formation. Inactivation of the cross-bridge cycle enables the myocardium to relax and then fill with blood during diastole. directly alter cellular processes within the heart, independent of temperature. While this is of prime importance to cardiac function, Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 allow the heart to remain functional over a range of physiological possibly on the I window current (see Vornanen, 1998), which Ca 2+ temperatures, including low temperatures. Churcott et al. (1994) occurs when L-type Ca channels that have inactivated reopen demonstrated that trout cardiac actin-myosin ATPase activity was during the action potential plateau. As the action potential duration 2+ more Ca sensitive than that from rats when compared at their is extended during cooling, it can allow a larger I window current. Ca respective physiological temperature and pH (7°C, pH 7.2 vs 37°C, It is important to note that in some species, like bluefin tuna, the 2+ pH 6.78 for trout and rat, respectively). Moreover, the authors found drop in Ca influx during cooling is not completely compensated 2+ that the Ca concentration required by trout cardiac muscle for by the increased action potential duration. In these hearts, preparations to reach half maximal tension was approximately one- adrenaline, which is thought to be released during dives into cold 2+ tenth that of rat cardiac tissue when tested at the same experimental water, augments Ca influx through voltage-gated ion channels. 2+ 2+ temperature (Fig. 1). This higher Ca sensitivity of the trout cardiac This increased Ca influx combines with a prolonged action 2+ tissue is believed to be one mechanism that helps to offset the potential duration to restore force-generating Ca flux into the cardioplegic effects (see Glossary) of cold on the trout heart myocytes during temperature changes of >10°C (Shiels et al., (Blumenschein et al., 2004; Gillis et al., 2003a). These interactions 2015). 2+ will be discussed further in the section ‘Myofibril remodelling’. Although this trade-off between action potential duration and Ca 2+ influx can maintain adequate Ca influx to allow the fish to cope Acute effects on ion channel flux and the action potential with short-term changes in temperature, it is less effective during 2+ 2+ Acute cooling reduces the flux of Ca (I , the Ca current) prolonged thermal acclimation. Indeed, during chronic (days to Ca 2+ + through voltage-gated Ca channels into the myocyte (Fig. 2), weeks) cold exposure there is a remodelling of potassium (K ) which can directly reduce the contractility of the heart at cold channel expression that serves to reverse the increase in action temperatures. This is because I is the primary source of the potential duration. This is important, as a prolonged action potential Ca 2+ activating Ca that triggers cross-bridge cycling. In fish species that can be pro-arrhythmic and also may compromise electrical restitution 2+ utilize intracellular Ca stores of the sarcoplasmic reticulum (SR) (the recovery of an action potential as a function of the diastolic in the activation of muscle contraction [e.g. rainbow trout (Hove- interval). These temperature-induced alterations in the ion channels Madsen and Tort, 1998; Shiels and White, 2005); burbot (Lota lota; of the fish heart are discussed in detail in a recent review (Vornanen, Shiels et al., 2006b); yellowfin tuna (Thunnus albacares; Shiels 2016). Together, the effects of an acute decrease in temperature on et al., 1999); bluefin tuna (Thunnus orientalis; Shiels et al., 2011); electrical and mechanical function lead to a reduction in the force Box 1], the reduction in I has a cascading effect: a reduced of cardiac muscle contraction (inotropic effects; see Glossary), Ca 2+ amplitude of I reduces the trigger for SR Ca release, thus illustrating the need for temperature-dependent remodelling to Ca 2+ reducing the amount of Ca available to interact with the preserve the active pumping properties of the fish heart during myofilaments and initiate cross-bridge cycling. chronic temperature change. Some of the direct effects of reduced I during cooling can be Ca offset by other temperature-induced changes in the electrical Acute effects on the diastolic properties of the heart properties of the heart. For example, acute cooling increases the An acute temperature change also influences the resting, non-force duration of the ventricular action potential [e.g. rainbow trout generating properties of the heart by affecting the passive properties (Shiels et al., 2000); bluefin tuna (Galli et al., 2009); pink salmon of the myocardium. For example, an increase in temperature (Oncorhynchus gorbuscha) (Ballesta et al., 2012)]. This allows decreases the contribution of viscous tension, viscoelastic tension 2+ more time for Ca influx during the action potential plateau, and elastic tension to cardiac stiffness (see Glossary), resulting in 6.5 Membrane potential (mV) –80 –60 –40 –20 0 20 40 60 80 6.0 –1 5.5 5.0 –5 14°C 21°C 4.5 7°C 0 5 10 15 20 25 30 Temperature (°C) –7 2+ 2+ Fig. 1. Ca sensitivity of force generation by skinned ventricular fibres Fig. 2. Trans-sarcolemmal Ca flux varies in trout cardiac myocytes with 2+ 2+ over a range of temperatures. pCa is the Ca concentration required to acute temperature changes. Acute reductions in temperature reduce Ca flux 2+ generate half-maximum force. When compared at the same temperature, trout through L-type Ca channels in rainbow trout atrial myocytes. All values are 2+ ventricular fibres require 10 times less Ca than those from the rat to generate means±s.e.m. The values for I (pA) are normalized from the measured cell Ca −1 the same amount of force. Figure adapted from Churcott et al. (1994). capacitance to give the value in pA pF . Figure adapted from Shiels et al. (2000). pCa –1 Peak I (pA pF ) Ca Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 decreased passive stiffness (Mutungi and Ranatunga, 1998). 2.5 Together, the changes in the non-force-generating properties of 5°C the muscle caused by a change in physiological temperature 10°C 2.0 18°C represent a potential challenge for the maintenance of normal cardiac function. It is, therefore, not surprising that factors which 1.5 contribute to the passive properties of the heart, such as collagen content and composition, are modified in response to thermal 1.0 acclimation (Keen et al., 2016; Klaiman et al., 2011; Johnson et al., 2014). 0.5 Cardiac remodelling following chronic temperature change Evidently, acute temperature change is a challenge for maintained 0.075 0.175 0.275 0.375 0.475 0.575 0.675 cardiac function in fishes. Thus, prolonged temperature change Volume (ml) results in remodelling of all aspects of cardiac function. For example, in relation to the direct effects of acute cooling discussed Fig. 3. Thermal remodelling of ventricular compliance in the rainbow above, cold acclimation results in an increase in basal heart rate trout. Ex vivo pressure–volume relationships show increased passive stiffness (Haverinen and Vornanen, 2007; Keen et al., 1993; Lurman et al., of the whole ventricle following cold acclimation (5°C) compared with controls 2012), maximum stroke volume (Driedzic et al., 1996; Farrell, (10°C), and increased compliance following warm acclimation (18°C). Data points show the means±s.e. All lines are significantly different from each other, 1991; Lurman et al., 2012), maximum power output (Bailey and assessed via GLM. Figure is adapted from Keen et al. (2016). Driedzic, 1990; Lurman et al., 2012) and maximum cardiac output (Lurman et al., 2012), as well as a greater sensitivity to β-adrenergic stimulation (Keen et al., 1993). For excellent reviews of energetics influenced at the organ level by the pericardium and by the geometry and electrical activity associated with thermal acclimation in fishes and thickness of the ventricular walls. In fish, the ratio of spongy to see Driedzic and Gesser (1994), Vornanen et al. (2002) and compact tissue is also likely to contribute to cardiac compliance, with Vornanen (2016). Below, we focus on the active and passive compact myocardium being stiffer than spongy myocardium. changes associated with structural remodelling of the fish heart. Historically, ventricular wall thickness and connective tissue content were thought to be the dominating factors driving Phase 1 – Diastolic filling of the ventricle ventricular compliance; however, there is now evidence to suggest The first stage of the cardiac cycle is diastolic filling. As the that there are important contributing roles for many extracellular and ventricle relaxes, ventricular pressure decreases. When ventricular intracellular mechanisms. In fish hearts, it is likely that a combination pressure drops below atrial pressure, the atrioventricular valve opens of factors determine overall passive stiffness. and blood flows from the atrium into the ventricle. This phase of the The main components of the cardiac extracellular matrix (ECM) cardiac cycle is known as isovolumic relaxation, and it lasts from the are the interstitial fibrous proteins, collagen and elastin and time when the atrioventricular valves open until they close again. glycosaminoglycans, which connect to ECM proteins to form Ventricular pressure and, therefore, diastolic filling volume are proteoglycans (Cleutjens and Creemers, 2002; Fomovsky and largely determined by cardiac preload, which is determined by Holmes, 2010). The elastic elements of the ECM (collagen and venous pressure and atrial systole. The sinus venosus and atrium are elastin) provide structure and support to the chamber walls and are, larger than the ventricle and act as reservoirs by modulating the therefore, central to the overall passive tension of the ventricle volume of blood entering the heart (Farrell, 1991). To maintain (Katz, 2006). Matrix proteins also surround individual myocytes, correct diastolic function, the ventricle must be compliant enough to muscle bundles and blood vessels, forming a complex structural allow sufficient filling, but also needs to be strong enough to network of interstitial matrix and basement membrane (Sanchez- withstand the haemodynamic stress of pumping a large volume of Quintana et al., 1995). Together, this network of proteins helps to blood. Passive tension describes the resistance of a cardiac chamber maintain the structural integrity of the heart while also enabling – to diastolic filling and, therefore, plays a role in the Frank–Starling and controlling – the distensibility (i.e. the fold change in cardiac response of the heart (Shiels and White, 2008), where an increase in compliance) of the tissue. end-diastolic volume results in an increase in systolic contraction Collagen is the most common structural protein in the ECM and stroke volume. In rainbow trout, passive stiffness of the whole (Fomovsky and Holmes, 2010). It forms stiff fibres that support and ventricle increases following cold acclimation, as shown by maintain the alignment of myocytes by bearing wall stress. At high generating ex vivo pressure–volume relationships (Fig. 3) (Keen chamber volumes, the collagen fibres become stiff and straight to et al., 2016). Functionally, these decreases in chamber compliance resist overexpansion and damage to myocytes (Fomovsky and (see Glossary) may be cardioprotective, by providing support to the Holmes, 2010). In mammals, chronic increases in cardiac load are cardiac wall to counteract the increased haemodynamic stress often associated with increased myocardial collagen deposition, encountered during high cardiac load. However, excessive which allows the heart to resist the increased haemodynamic stiffening of the myocardium has been shown in mammals to stress. Collagen also increases the passive stiffness of the chamber reduce diastolic filling and, in severe cases, can lead to diastolic wall, so excessive fibrosis of the myocardium can reduce chamber dysfunction (Collier et al., 2012). It is currently unclear how compliance and chamber distensibility, which can have implications increased diastolic stiffness affects in vivo diastolic filling in fish. for diastolic filling (Collier et al., 2012). In the fish heart, collagen can These features are discussed in more detail below. be identified using PicroSirius Red staining, and it is visible in both the compact and spongy myocardium (Fig. 4A,B). In rainbow trout, Stiffness, compliance and the extracellular matrix myocardial fibrillar collagen content (Keen et al., 2016; Klaiman The end-diastolic pressure–volume relationship describes myocardial et al., 2011) and/or connective tissue content (Keen et al., 2016; relaxation. This relationship, and therefore cardiac compliance, is Klaiman et al., 2011) increases ∼1.7-fold and ∼3.5-fold, respectively, Pressure (kPa) Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 Rainbow trout Zebrafish Pericardial membrane Pericardial membrane A B Pericardial membrane Pericardial membrane Spongy myocardium Compact myocardium Compact myocardium Spongy myocardium Spongy myocardium Compact myocardium Compact myocardium Spongy myocardium Collagen content Thin/diffuse collagen Thick/dense collagen C D † † 0.4 Control Cold Control Cold 0.3 0.2 4 30 0.1 Control Cold Control Cold Compact myocardium Spongy myocardium Gene expression 2.0 a a EF 3.0 2.5 12 * 1.5 2.0 1.5 1.0 1.0 b 0.5 a c 0 0 0.5 Control Cold Control Cold 2.0 4 * 1.5 1.0 1.0 0.5 c 0 0 0.8 Control Cold Control Cold 2.0 2.5 0.6 b 2.0 1.5 0.4 b b 1.5 1.0 c 1.0 0.2 0.5 0.5 Control Cold Control Cold Fig. 4. Thermal remodelling of ventricular collagen in rainbow trout and zebrafish. Representative bright-field (left) and polarised-light (right) micrographs of control (A) rainbow trout and (B) zebrafish ventricular tissue sections stained with PicroSirius Red, which allows semi-quantification of fibrillar collagen content. Cold acclimation causes an increase in ventricular collagen content in (C) rainbow trout, but (D) a decrease in thick collagen fibres in the zebrafish ventricle. (E) Increased ventricular collagen content in rainbow trout is associated with increased mRNA expression of collagen-promoting genes (5°C; blue), compared with control (10°C; green), whereas warm acclimation (18°C; red) is associated with an increase in mRNA expression of collagen-degrading genes. (F) Following cold acclimation, zebrafish ventricles show an increase in mRNA expression of collagen-regulatory genes, suggesting increased collagen turnover. In the zebrafish experiment fish were maintained at 27°C (Control) or acclimated to 20°C (cold). All data are means±s.e. Letters and symbols indicate significant differences. Figures modified from Johnson et al. (2014) and Keen et al. (2016). Scale bars: 100 μm. Cold Control Warm Cold Control Warm Col1a1 Col1a2 Col1a3 TIMP2 MMP2 MMP9 MMP13 mRNA expression/β-actin Spongy collagen (%) Compact collagen (%) COL1A2/EF1α MMP13/EF1α MMP2/EF1α mRNA level mRNA level mRNA level Proportion of total Area (μm) collagen (%) TIMP2/EF1α MMP9/EF1α COL1A1/EF1α mRNA level mRNA level mRNA level Area (μm) Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 following cold acclimation (Fig. 4C), which is likely to protect the trout following thermal acclimation. Comparatively, in mammals, myocardium from the increased haemodynamic stress of pumping total cardiac connective tissue increases of ∼1.6-fold are considered cold viscous blood. However, the opposite response has been to be a pathological condition that stiffens the myocardium, which is observed in zebrafish, where there is significantly less thick collagen often associated with ∼1.3- to 2.1-fold increases in the ratio of type fibres in the hearts of fish acclimated to 20°C compared with those I:type III collagen – type I collagen is less extensible than type III acclimated to 28°C (Fig. 4D) (Johnson et al., 2014). One potential (Jalil et al., 1988, 1989; Marijianowski et al., 1995; Pauschinger explanation for these opposing responses is related to the difference in et al., 1999). Such changes are common, and permanent, in the blood pressure between zebrafish and trout. Adult zebrafish weigh hearts of patients suffering from cardiac hypertension, dilated between 0.3 and 1.0 g (Fuzzen et al., 2010) and measurements cardiomyopathy or chronic congestive heart failure, and they completed by Hu et al. (2001) indicate that peak ventricular pressure contribute to the associated diastolic dysfunction and eventual heart in these fish is 3 mmHg. Meanwhile, the blood pressure of ∼750 g failure (Jalil et al., 1988, 1989; Marijianowski et al., 1995; trout is approximately 50 mmHg (Clark and Rodnick, 1999). This Pauschinger et al., 1999). The ability of fish species, including suggests that there is less pressure to inflate the zebrafish heart. the zebrafish and trout, to regulate myocardial collagen content in Therefore, an increase in the stiffness of the zebrafish myocardium response to changes in physiological conditions suggests that fish caused by an acute decrease in temperature would make it more show greater cardiac phenotypic plasticity than mammals. difficult for the lacunae in the zebrafish heart to fill with blood during diastole. Further work is required to compare how cold acclimation Intracellular contribution to stiffness and compliance influences the passive stiffness of trout and zebrafish hearts. At the myocyte level, cardiac compliance during diastolic filling is However, recent work by Lee et al. (2016) using high-resolution influenced by a number of features. Firstly, the amount and speed of 2+ + 2+ echocardiography demonstrates that cold acclimation of zebrafish Ca removal from the cytoplasm by the SR and the Na /Ca does not alter the early peak velocity:atrial peak velocity (E/A) ratio exchanger alters stiffness and compliance through residual active 2+ (i.e. the ratio of early ventricular filling, where blood flows into the tension. The Ca affinity of troponin and the dissociation of 2+ ventricle solely due to pressure gradient, to ventricular filling aided by contractile proteins once Ca has dissociated from troponin (Katz, atrial contraction, which is the second phase of atrial filling), 2006) influences this relationship. Secondly, passive stiffness of the indicating that there was no loss of diastolic function. This study also cytoskeleton and of sarcomeric proteins such as titin plays a large role demonstrated that cold-acclimated fish had a slower isovolumetric in determining overall myocyte stiffness and compliance (Granzier contraction time compared with warm-acclimated fish when et al., 1996; Horowits et al., 1989; Shiels and White, 2008; Watanabe measured at 18°C (Lee et al., 2016). This suggests that cold- et al., 2002). Titin is a giant sarcomeric protein that runs from the acclimated fish show improved ejection, and that the zebrafish is able Z-line through to the M-line (Helmes et al., 1996; Linke, 2008; Linke to effectively compensate for the influence of low temperature on et al., 1996; Peng et al., 2007; Wu et al., 2000). Two titin isoforms cardiac function following cold acclimation. exist in the vertebrate adult heart: a shorter and stiffer N2B isoform Myocardial collagen content reflects a balance between collagen and a longer and more compliant N2BA isoform (Cazorla et al., 2000; deposition and degradation. Collagen degradation is regulated by Patrick et al., 2010). The ratio of the two isoforms modulates titin- matrix metalloproteinase (MMPs), and the gelatinase activity of based passive tension (Cazorla et al., 2000; Fukuda et al., 2005; MMPs is regulated by tissue inhibitors of MMPs (TIMPs). Linke, 2008; Trombitas et al., 2001). In addition, phosphorylation of Increased enzymatic activity of TIMPs inhibits collagen the N2B element by protein kinase A (PKA) or protein kinase G degradation by MMPs, and is associated with increased collagen (PKG) can decrease passive force (Krüger and Linke, 2009). Cardiac deposition. With cold-induced ventricular hypertrophy and fibrosis output in the rainbow trout heart can be modulated by up to 3-fold in rainbow trout, myocardial expression of MMP2 and MMP13 increases in stroke volume. Therefore, it is perhaps unsurprising that mRNA is downregulated (Keen et al., 2016), and there is an rainbow trout ventricular myocytes have a higher ratio of the associated upregulation of TIMP2 mRNA transcripts (Fig. 4E) compliant N2BA isoform to the stiffer N2B isoform compared with a (Keen et al., 2016). Conversely, cold acclimation of zebrafish – rat myocyte (Patrick et al., 2010). However, passive tension remains which causes a decrease in collagen content and in the proportion of higher in a fish myocyte than a rat myocyte due to a lower level of titin thick collagen fibres in the compact myocardium – is associated phosphorylation, which may explain the large Frank–Starling with an increase in the level of gene transcripts for MMP2 and response in fish hearts (Patrick et al., 2010). MMP9 in the heart (Fig. 4F) (Johnson et al., 2014). This suggests At present, the effect of temperature acclimation on the that there is an increase in collagen turnover that would result in the intracellular structure and titin remodelling in the fish heart is not observed changes in collagen content (Johnson et al., 2014), and is known. In mammals, the expression of specific titin isoforms shows further evidence that MMPs play a role in regulating collagen plasticity, with the changing haemodynamics that occur during content in the fish heart during thermal acclimation. cardiac growth altering titin ratios, but little is known about the The predominant fibrillar collagen in cardiac tissue is collagen I, mechanism (Linke, 2008). The ratios of titin isoforms have been followed by collagen III (Eghbali and Weber, 1990). Fibrillar suggested to shift to compensate for cardiac fibrosis by increasing collagen molecules are made by super-coiling three alpha amino the expression of the compliant N2BA isoform (Neagoe et al., acid chains into an α-helix. In mammals, collagen I is composed of 2002). However, increased compliance of titin may reduce systolic two type 1 (α1) and one type 2 (α2) subunits. However, in collagen I function via the Frank–Starling mechanism because of reduced titin of bony fishes, one of the α1 chains is replaced with a type 3 (α3) spring activity (Linke, 2008). In fish, the titin isoform ratio is also subunit (Saito et al., 2001). Keen et al. (2016) showed this fish- likely to be an important feature for determining the passive specific α3 chain is upregulated 1.4-fold with the cold-induced properties of the fish heart. Keen et al. (2016) demonstrated this in fibrosis observed in the trout heart. Interestingly, the α3 chain rainbow trout by measuring micromechanical stiffness of reduces the denaturation temperature of the collagen I molecule and ventricular tissue sections with atomic force microscopy. Cold makes it more susceptible to degradation by MMP13 (Saito et al., acclimation increased micromechanical stiffness by ∼1.9-fold (to 2001), which may explain the transient nature of cardiac fibrosis in ∼0.85 MPa), which is comparable to the stiffness recorded in Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 scarred mammalian myocardium following myocardial infarction until an SL of 2.6 μm. Since the trout heart has a high ejection (∼0.8 MPa) (Hiesinger et al., 2012). Furthermore, cumulative fraction volume (>80%; Franklin and Davie, 1992), this would allow frequency curves showed an even distribution of tissue stiffness, the ventricle to be stretched to a greater extent, and as a result, allow suggesting that tissue stiffness was increasing evenly across the for greater diastolic filling and increased strength of contraction. tissue rather than due to specific increases in the stiffness of the These factors are critical to the regulation of cardiac output via the structural components of the tissue, such as fibrillar collagen. Future Frank–Starling mechanism in fish (Shiels et al., 2006a). studies should aim to understand the changes in the intracellular structure of the fish myocyte that occur with temperature Myofibril remodelling acclimation and how these contribute to the overall changes in Force is produced in striated muscle by the cycling of cross-bridges passive tension of the fish ventricle. between the actin thin filaments and myosin thick filaments. This 2+ reaction, initiated by Ca binding to the thin filament, results in Cardiac hypertrophy muscle contraction. One mechanism for regulating contractile In mammals, wall thickness is known to affect passive stiffness of function in skeletal or cardiac muscle in the face of an the ventricle, therefore hypertrophy (muscle growth) or atrophy environmental stressor is to express an isoform of a protein that is (muscle loss) of the ventricle may influence the diastolic filling better suited for a particular physiological condition. For example, phase of the cardiac cycle. In the mammalian heart, hypertrophy is Crockford and Johnston (1990) demonstrated that cold acclimation of initiated by increased cardiac load caused by physiological carp resulted in the expression of a unique myosin light chain (MLC) stressors, including aerobic exercise and pregnancy, or a in skeletal muscle and also increased the expression of MLC-1 while pathological condition, such as a myocardial infarction or decreasing the expression of MLC-3. Previous work by Vornanen hypertension (Dorn, 2007; Dorn et al., 2003). The elevated (1994) has demonstrated that one isoform of MHC is expressed in the biomechanical strain of chronic pressure or volume overload skeletal muscle of carp in winter but that two isoforms are expressed in causes increased tension of the heart wall, which triggers the same muscle in summer. These changes in protein expression increased mRNA production and protein synthesis leading to correlate with altered myocyte contractility (Crockford and Johnston, cellular hypertrophy and increased connective tissue (Bishop, 1990; 1990; Vornanen, 1994). In the trout heart, cold acclimation has been Nadal-Ginard et al., 2003). Capillary growth is vital to provide the shown to alter the gene transcript levels for different isoforms of growing cardiac muscle with a sufficient supply of oxygen and cardiac myofilament proteins. More specifically, Genge et al. (2013) nutrition; thus, the secretion of angiogenic factors, such as vascular identified transcripts for two isoforms of TnC in the trout heart that endothelial growth factor (VEGF) is also observed (Weber and are modulated by cold acclimation. Troponin C (TnC) is the 2+ Janicki, 1989). Ca -activated trigger that initiates myocyte contraction (Box 1), A number of studies have shown increased ventricular mass and previous studies have demonstrated that manipulation of the (relative to body mass) in fish following cold acclimation (Aho and isoform working in the muscle can alter contractile function (Gillis Vornanen, 1998; Driedzic et al., 1996; Farrell et al., 1988; Kent et al., 2005). In addition, Alderman et al. (2012) demonstrated that the et al., 1988; Klaiman et al., 2011; Vornanen et al., 2005). The trout heart expresses the gene transcripts for seven different TnI increased ventricular mass is mainly attributed to an increase in isoforms, and that the abundance of four of these changes with cold myocyte size, suggesting it is a physiological hypertrophic acclimation. There are considerable differences within the sequences response, in the spongy layer (Aho and Vornanen, 1998; Driedzic of the seven TnI isoforms found in trout heart (Alderman et al., 2012), et al., 1996; Keen et al., 2016; Klaiman et al., 2011; Vornanen et al., which likely result in differences in the functional properties of the 2005). However, some studies suggest that myocyte hyperplasia protein. If the changes in TnI transcript abundance translate into (increase in cell numbers) accounts for around 20% of myocardial changes in the complement of protein isoforms present in the muscle, 2+ growth, in addition to hypertrophy (Farrell et al., 1988; Keen et al., this would potentially alter the Ca sensitivity or the kinetics of 2016; Sun et al., 2009). The mRNA expression of VEGF is contraction. Such a strategy may be utilized to maintain contractile upregulated during cold acclimation, suggesting an increased blood function in the trout heart with cold acclimation. supply to the compact layer (Jørgensen et al., 2014; Keen et al., Phosphorylation of key regulatory proteins – including cardiac 2016). This hypertrophic response upon cold acclimation, along troponin I (cTnI), cardiac troponin T (cTnT) and myosin binding with the increase in cardiac connective tissue, indicates that changes protein C (MyBP-C) – can modulate myofilament function in the in physiological conditions can elicit a significant phenotypic vertebrate heart (reviewed by Shaffer and Gillis, 2010). In the response as the heart continues to function. mammalian heart, these proteins can be targeted by protein kinase A (PKA) or protein kinase C (PKC) following β-adrenergic or Phase 2 – Pressure generation α-adrenergic stimulation, respectively (Shaffer and Gillis, 2010). The second stage of the cardiac cycle is pressure generation. The resultant functional changes that follow PKA phosphorylation 2+ Following ventricle filling, the ventricular myocardium starts to in the mammalian heart include a decrease in the Ca sensitivity of 2+ contract isometrically, building up pressure within the ventricle, force generation, increased kinetics of Ca activation and a which closes the atrioventricular valve. An increase in end-diastolic decrease in force generation (Chandra et al., 1997; Dong et al., volume results in an increase in systolic contraction and stroke 2007). Using a chemically skinned myofilament preparation from volume (Frank–Starling response). At the cellular level, an increase trout hearts, it has been shown that PKA phosphorylation decreases in pressure during ventricle loading stretches the myocytes in the cross-bridge cycling and maximal force generation (Gillis and ventricle, increasing sarcomere length (SL) and, thus, changing the Klaiman, 2011). Interestingly, cold acclimation of trout results in an force of contraction (reviewed in Shiels and White, 2008). increase in the maximal rate of the cardiac actomyosin-ATPase Mammalian cardiac myocytes show an increase in the force of activity (Klaiman et al., 2014; Yang et al., 2000) (Fig. 5A), an 2+ contraction with an increase in SL until a peak of ∼2.2 μm (Gordon increase in the Ca sensitivity of force generation by skinned et al., 1966); however, Shiels et al. (2006a) have demonstrated that ventricular trabeculae (see Glossary; Klaiman et al., 2014) (Fig. 5B) the active force of contraction in trout cardiac myocytes increases as well as an increase in the magnitude and rate of pressure Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 Fig. 5. Cardiac contractile properties A 4°C of trout acclimated to 4°C, 11°C and 11°C 17°C 17°C. (A) The maximal activity of 2+ actomyosin Mg -ATPase isolated from ventricles is higher in preparations from cold-acclimated trout than those from warm-acclimated trout when measured 2+ at 17°C. (B) The Ca sensitivity of force generation by cardiac trabeculae from trout acclimated to 4°C (blue line) is greater than that of trabeculae from trout acclimated to 11°C (black line) or 17°C (red line) when measured at 15°C. 20 pCa is the pCa at half-maximum force. SL, sarcomere length. (C) Developed pressures at ventricle volumes greater 17°C, pH=7 than baseline are higher for the 4°C acclimated (blue symbols) fish than 8.0 7.5 7.0 6.5 6.0 5.5 5.0 those for the 11°C (black symbols) and pCa 17°C (red symbols) acclimated fish. Circles indicate ventricular developed pressures, while squares indicate pCa diastolic pressures. All data are means± 1.0 4°C 5.69±0.03 s.e. Figures modified from Klaiman et al. 11°C 5.61±0.01 (2011) and Klaiman et al. (2014). The 17°C 5.59±0.02 images on the right of the panels are: (A) 0.8 a schematic of a thick and thin filament inside a cardiac myofilament; (B) a micrograph of a trout cardiac 0.6 myofilament preparation attached to a force transducer and servo motor via aluminium clips; and (C) a schematic of 0.4 a trout heart. 0.2 15°C, pH=7, SL=2.2 μm 6.2 6.0 5.8 5.6 5.4 5.2 pCa 010 20 30 40 50 60 Balloon volume (μl) generation by the isolated heart (Fig. 5C) (Klaiman et al., 2014). are due, at least in part, to post-translational changes in the This indicates that the heart functions better with cold acclimation myofilament regulatory proteins (Klaiman et al., 2011, 2014). (Klaiman et al., 2014). Quantification of phosphorylation of the myofilament proteins in the cold-acclimated hearts demonstrates a Cardiac morphology decrease in the phosphorylation of cTnT, slow skeletal TnT and Cardiac hypertrophy following cold acclimation in fish is a MyBP-C. This suggests that the changes in myofilament function strategy to help compensate for the effect of low temperature on 2+ Actomyosin Mg -ATPase activity –1 –1 Ventricular pressure (mmHg) Normalized force generation (nmol Pi min mg ) Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 Spongy myocardium Compact myocardium Com 1,2,3 1,2,3 M Myocyte bundle hypertrophy Compact thickness C 1,3 1,2,3 Extra-bundular sinus E Fibrillar and amorphous collagen F mRNA m of muscle growth genes Whole chamber passive stif W fness 3 3 mRNA m of hypertrophic markers Micromechanical stif M fness of tissue mRNA m of collagen-promoting genes 5 Cellular lipid droplets C mRNA m of collagen-degrading Cellular glycogen C 17–18°C genes g 1,2,3 Amorphous collagen A Whole chamber passive W stif s fness Cellular lipid droplets C Cellular glycogen Blood to ventral aorta Bulbus arteriosus Ventricle (compact myocardium) Atrium 10–11°C Ventricle (spongy myocardium) Sinus venosus Venous blood from cardinal and hepatic veins 1,2,3 Myocyte bundle hypertrophy M 1,2,3 Compact thickness C 1,3 Extra-bundular sinus Ex Fibrillar and amorphous collagen F 3,4 mRNA m of muscle growth genes 3 Whole chamber passive stif W fness 4–5°C mRNA m of hypertrophic markers 3 T Tissue micromechanical stiffness mRNA m of collagen-promoting genes 5 Cellular lipid droplets C mRNA m of collagen-degrading genes Cellular glycogen 1,2,3 Amorphous collagen A Whole chamber passive stif W fness T Tiissue micromechanical stiffness Cellular lipid droplets C Cellular glycogen Fig. 6. Thermal remodelling of the rainbow trout heart. A summary of the effects of chronic cooling (5°C) and chronic warming (18°C) on the rainbow trout 1 2 3 4 heart, compared with those of fish kept at control temperature (10°C). Klaiman et al., 2011; Klaiman et al., 2014; Keen et al., 2016; Vornanen et al., 2005; 5 6 Driedzic et al., 1996; Driedzic and Gesser, 1994. the active properties of the muscle by increasing muscle mass, above). In this study, there were also changes to the morphology thus increasing the pressure-generating ability of the myocardium of the heart (Klaiman et al., 2014), including a decrease in the (Driedzic et al., 1996; Gamperl and Farrell, 2004; Graham and relative proportion of compact myocardium and a reciprocal Farrell, 1989; Keen et al., 2016; Klaiman et al., 2011). However, increase in spongy myocardium (Fig. 6 and Table 1). Such a recent work by Klaiman et al. (2014) demonstrated that cold change in cardiac morphology with cold acclimation has been acclimation of trout can increase the pressure-generating capacity reported in other studies of trout (Farrell et al., 1988; Keen et al., of the heart in the absence of a hypertrophic response (Fig. 5C). 2016; Klaiman et al., 2011), as well as for zebrafish (Johnson This change in function is likely to be due, at least in part, to et al., 2014). In the fish heart, the spongy myocardium is alterations of the myofilaments (see ‘Myofibril remodelling’ composed of trabecular sheets that enable the formation of Journal of Experimental Biology A A U U U T T T C C G G G A A A G G G A A C C T T C C REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 Table 1. Integrated remodelling response of the rainbow trout ventricle following prolonged cold exposure, across multiple levels of biological organization Response References Gene expression Anti-sense strand Anti-sense strand Vornanen et al., 2005; Keen et al., 2016 ↑ mRNA of muscle growth genes ↑ mRNA of hypertrophic markers Keen et al., 2016 mRNA mRNA ↑ mRNA of collagen promoting genes Keen et al., 2016 ↓ mRNA of collagen degrading genes Keen et al., 2016 G G G G ↑ VEGF expression Keen et al., 2016 C C Sense strand Senses estrand Myofilaments Tnc Tm ↑ AM-ATPase Yang et al., 2000; Klaiman et al., 2011 Tnl Actin TnT ↑↓ Gene expression of 4 TnI isoforms and 2 Alderman et al., 2012; Genge et al., 2013 cTnC isoforms ↓ Phosphorylation of TnT Klaiman et al., 2014 Myosin S1 cMyBP-C C0 C1 Myosin S2 C2 C3 C4 C5 C6 C7 C8 C9 C10 ELC Titin LMM RLC Calcium handling 2+ RyR Keen et al., 1994; Aho and Vornanen, 1998, 1999 ↑ Rate of SR Ca release/uptake 2+ SERCA Ca PLB ↑ SERCA transcript expression Korajoki and Vornanen, 2012 NCX ↑ β-adrenergic receptor density and sensitivity Graham and Farrell, 1989; Keen et al., 1993; Aho 3 Na SR and Vornanen, 2001 ∼ RyR density and localization Birkedal et al., 2009 2+ DHPR Ca MF 2+ Ca NCX 2+ SL Ca ATPase 3 Na Myocyte Aho and Vornanen, 1999 ↑ Rate of contraction (intact muscle) ↓ Refractoriness Aho and Vornanen, 1999 2+ ↑ Ca sensitivity of skinned trabeculae Klaiman et al., 2014 Whole heart ↑ Heart size Farrell et al., 1988; Graham and Farrell, 1989; Atrium Sinus Vornanen et al., 2005; Birkendal et al., 2009; venosus Klaiman et al., 2011; Keen et al., 2016a Bulbus ↑ Connective tissue content Klaiman et al., 2014 arteriosus ↑ Fibrillar collagen content Keen et al., 2016 ↓ Compact layer thickness Farrell et al., 1988; Klaiman et al., 2014 ↑ Heart rate Aho and Vornanen, 2001 ↑ Passive stiffness Keen et al., 2016 ↑ Magnitude and rate of developed pressure Klaiman et al., 2014 Ventricle + 2+ Tm, tropomyosin; LMM, light meromyosin; RLC, regulatory light chain; ELC, essential light chain. NCX, Na /Ca exchanger; RyR, ryanodine receptor; SERCA, 2+ sarcoplasmic endoplasmic reticulum Ca -ATPase; PLB, phospholamban; DHPR, dyhydropyridine receptor. On all panels an upwards arrow indicates an increase, a downwards arrow indicates a decrease and the two arrows together indicate a change; ∼ indicates no response. G G C C C C C C G G G U U A A A Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 lacunae that fill with blood during diastole. Then, during systole, preload, and therefore ejection fraction, is primarily determined by the ventricular trabeculae act as ‘contractile girders’, helping to late diastolic filling, which is dependent on atrial contraction (Farrell pull the compact myocardium inwards during contraction and Jones, 1992; Lee et al., 2016). (Pieperhoff et al., 2009). Additionally, the small lacunae that are formed by the trabecular nature of the spongy muscle lower Influence of warm acclimation on the structure and function the wall tension against which the myocytes have to work, i.e. of the heart the trabeculae reduce the cardiac work load as explained by When the temperature of ventricular trabeculae from Atlantic cod LaPlace’s law. This functional organization of the myocardium is was increased from 10 to 20°C, the amount of work required to thought to enable the extremely high ejection fraction of the trout lengthen the preparations nearly doubled (Syme et al., 2013). The heart (∼80%) compared with that of the mammalian heart (50– authors suggest that this was due to an increase in the resting tension 60%), which does not contain spongy myocardium (Franklin and of the muscle (Syme et al., 2013). Such a response could be caused 2+ Davie, 1992). The observed increase in spongy myocardium seen by the increase in temperature enhancing the Ca sensitivity of the in the trout heart with cold acclimation would, therefore, increase myofilament, thereby increasing the number of active cross-bridges the stroke volume of the heart while also increasing the relative during diastole (Gillis et al., 2005, 2000, 2003b; Gillis and Tibbits, proportion of contractile machinery. Such a change would make 2002). This effect would stiffen the muscle, impair cardiac filling the heart able to pump more blood per contraction. and potentially limit the ability of the fish to maintain stroke volume as temperature rises (Syme et al., 2013). Therefore, just as the Length-dependent changes in force generation structure and function of the fish heart may remodel to (partially) Changes in the resting length of the sarcomere can affect the compensate for a decrease in ambient temperature, it may also strength of contraction and, thus, the pressure-generating capacity remodel to offset the effects of increased environmental of the ventricle. Interestingly, Klaiman et al. (2014) demonstrated temperatures. For wild fish, increases in ambient temperature may that the difference in developed pressure at higher ventricle be more complex than the decreases associated with winter cold, as volumes between hearts from cold- and warm-acclimated fish was flow, shade and water depth can all affect water temperature. As greater than at smaller ventricle volumes. One possible such, behavioural thermoregulation is likely to play a key role in explanation for this result is that the cardiac muscle of fish that keeping fish cool. However, as overall ambient temperature have been acclimated to high or low temperatures may respond increases with global climate change, ectothermic animals living differently to stretch. As discussed above, rainbow trout cardiac in temperate environments are likely to experience larger muscle has a larger working range of the Frank–Starling curve temperature fluctuations, including periods of higher than average compared with that of rats, as well as a longer optimal sarcomere temperatures during summer months. The ability of fish species to length (2.6 µm versus 2.2 µm) (Patrick, et al., 2010; Shiels et al., respond to acute and prolonged changes in temperature may 2006a; Cazorla et al., 2000). In addition, previous work in therefore be essential for their long-term survival. mammals has shown that following a physiological stressor such Although laboratory-based temperature acclimation studies do not as exercise training, cardiac tissue has a greater response to stretch capture the complexity of temperatures that fish may encounter in (known as length-dependent activation) (Diffee and Nagle, 2003). open water, they offer an insight into the physiological remodelling Thus, it is possible that length-dependent activation is more that may occur. For example Badr et al. (2016) demonstrated that prominent in the trout heart following acclimation to cold warm acclimation increases the temperature at which heart rate temperatures. This hypothesis deserves future investigation. becomes irregular in the roach Rutilus rutilus. In addition, Klaiman et al. (2014) demonstrated that there is a decrease in the magnitude Phase 3 – Ejection and rate of ventricular pressure generation in hearts from warm- The third stage of the cardiac cycle is ejection. Following pressure acclimated trout compared with control (11°C) and cold-acclimated generation by the myocardium, the bulbo-ventricular valve opens, (4°C) fish when measured at a common experimental temperature and blood is forced from the ventricle into the bulbus arteriosus (Figs 5 and 6). Our groups have also demonstrated that warm in the fish outflow tract and from there to the rest of the body. In acclimation causes a reduction in overall ventricular mass, an increase zebrafish, ejection time decreases with acute reductions in ambient in the thickness of the compact layer, and a decrease in connective temperature; however, there are no effects following cold tissue content (Klaiman et al., 2011; Keen et al., 2016). The acclimation (Lee et al., 2016). Heart rate determines the duration decreased ventricular mass is attributed to a reduction in the area of between ejections. Although an acute decrease in temperature slows the spongy myocardium; therefore, morphologically, the ventricle heart rate (Driedzic and Gesser, 1994), cold acclimation results in shows the direct opposite response to that observed following cold partial thermal compensation (Aho and Vornanen, 1999; Little and acclimation. The increase in compact layer thickness and decrease Seebacher, 2014). The end result may increase isometric force in spongy layer thickness are linked to a functional increase in generation and thus ejection of blood from the ventricle. ventricular compliance (Keen et al., 2016), suggesting that the Conversely, stroke volume is not altered by acute temperature volume of blood being pumped per beat is reduced. As an increase in change (Clark et al., 2008; Gollock et al., 2006; Lee et al., 2016; physiological temperature increases heart rate in fish (Aho and Mendonca et al., 2007; Steinhausen et al., 2008), whereas during Vornanen, 2001; Badr et al., 2016; Lee et al., 2016), this suggests that chronic cooling it may remain constant or increase. Although Lee the heart is pumping less blood per beat at a faster rate. What is et al. (2016) showed that stroke volume peaks when ambient currently unknown, however, is whether and how the trout heart can temperature matches acclimation temperature, cold acclimation remodel to temperatures above its normal seasonal range, and what significantly increases systolic function, with increases in ejection the functional consequence of such remodelling is. fraction and fractional shortening, which is consistent with increases It is interesting to note that the cold-induced increase in collagen in the expression of contractile proteins (as explained above) (Genge deposition documented in the trout heart is reversed following et al., 2013). In zebrafish, acute temperature change does not affect chronic warming (Klaiman et al., 2011; Keen et al., 2016). In the E/A ratio, suggesting that – at all temperatures – ventricular contrast, in mammals collagen deposition can become relatively Journal of Experimental Biology REVIEW Journal of Experimental Biology (2017) 220, 147-160 doi:10.1242/jeb.128496 Bailey, J. R. and Driedzic, W. R. (1990). Enhanced maximum frequency and force fixed and is often the substrate for cardiac pathologies (arrhythmias, development of fish hearts following temperature acclimation. J. Exp. Biol. 149, diastolic dysfunction) in mammals (e.g. Nattel et al., 2008). Indeed, 239-254. in mammalian hearts, removing or reversing the trigger for Ballesta, S., Hanson, L. M. and Farrell, A. P. (2012). The effect of adrenaline on the temperature dependency of cardiac action potentials in pink salmon remodelling does not necessarily result in a reversion to the Oncorhynchus gorbuscha. J. Fish Biol. 80, 876-885. original state. The plasticity of the remodelling responses to Birkedal, R., Christopher, J., Thistlethwaite, A. and Shiels, H. A. (2009). warming and cooling is obviously well suited to a mesothermic Temperature acclimation has no effect on ryanodine receptor expression or fish such as the trout, but the mechanisms that permit these often subcellular localization in rainbow trout heart. J. Comp. Physiol. B 179, 961-969. Bishop, S. P. (1990). The myocardial cell: normal growth, cardiac hypertrophy and opposite responses are only just beginning to be examined. response to injury. Toxicol. Pathol. 18, 438-453. Blumenschein, T. M. A., Gillis, T. E., Tibbits, G. F. and Sykes, B. D. (2004). Effect Conclusions of temperature on the structure of trout troponin C. Biochemistry 43, 4955-4963. Boustany, A. M., Matteson, R., Castleton, M., Farwell, C. and Block, B. A. (2010). The ability of some fish to remodel their heart in response to Movements of pacific bluefin tuna (Thunnus orientalis) in the Eastern North Pacific changes in environmental temperature has ecological consequences, revealed with archival tags. Prog. Oceanogr. 86, 94-104. as it enables them to remain active over a wide range of Cazorla, O., Freiburg, A., Helmes, M., Centner, T., McNabb, M., Wu, Y., environmental temperatures. Such plasticity may also improve Trombitas, K., Labeit, S. and Granzier, H. (2000). Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ. Res. 86, 59-67. their ability to maintain cardiac function as average seasonal Chandra, M., Dong, W.-J., Pan, B.-S., Cheung, H. C. and Solaro, R. J. (1997). temperatures increase with global climate change. Independent of Effects of protein kinase A phosphorylation on signaling between cardiac troponin these potential advantages, the ability of fish to remodel their heart I and the N-terminal domain of cardiac troponin C. Biochemistry 36, 13305-13311. Churcott, C. S., Moyes, C. D., Bressler, B. H., Baldwin, K. M. and Tibbits, G. F. in response to changes in environmental conditions is a significant 2+ (1994). Temperature and pH effects on Ca sensitivity of cardiac myofibrils: a feat that results from significant phenotypic plasticity. Current and comparison of trout with mammals. Am. J. Physiol. 267, R62-R70. future studies should investigate how rapidly a fish heart can Clark, R. J. and Rodnick, K. J. (1999). Pressure and volume overloads are associated with ventricular hypertrophy in male rainbow trout. Am. J. Physiol. 277, remodel in response to a change in environmental temperature and R938-R946. examine the physiological consequences of multiple remodelling Clark, T. D., Taylor, B. D., Seymour, R. S., Ellis, D., Buchanan, J., Fitzgibbon, events. In addition, all known studies have looked at fixed time Q. P. and Frappell, P. B. (2008). Moving with the beat: heart rate and visceral points (6 or 8 weeks) of thermal acclimation and not at the time temperature of free-swimming and feeding bluefin tuna. Proc. R. Soc. B Biol. Sci. 275, 2841-2850. course of remodelling. Such information would be relevant to Cleutjens, J. P. M. and Creemers, E. E. J. M. (2002). Integration of concepts: understanding how stochastic environmental temperatures may cardiac extracellular matrix remodeling after myocardial infarction. J. Card. Fail. 8, affect natural fish populations. Such knowledge also has significant S344-S348. Collier, P., Watson, C. J., van Es, M. H., Phelan, D., McGorrian, C., Tolan, M., biomedical application by increasing our understanding of what Ledwidge, M. T., McDonald, K. M. and Baugh, J. A. (2012). Getting to the heart limits the ability of the vertebrate heart to remodel in response to a of cardiac remodeling; how collagen subtypes may contribute to phenotype. physiological stressor and providing novel insights useful for the J. Mol. Cell. Cardiol. 52, 148-153. development of strategies to control pathological remodelling seen Cortemeglia, C. and Beitinger, T. L. (2005). Temperature tolerances of wild-type and red transgenic zebra Danios. Trans. Am. Fish. Soc. 134, 1431-1437. in mammalian hearts. Crockford, T. and Johnston, I. A. (1990). Temperature acclimation and the expression of contractile protein isoforms in the skeletal muscles of the common Acknowledgements carp (Cyprinus carpio L.). J. Comp. Physiol. 160, 23-30. The authors thank Dr S. A. Alderman for editorial comments on an earlier version of Diffee, G. M. and Nagle, D. F. (2003). Exercise training alters length dependence of the manuscript. contractile properties in rat myocardium. J. Appl. Physiol. 94, 1137-1144. Dong, W.-J., Jayasundar, J. J., An, J., Xing, J. and Cheung, H. C. (2007). Effects Competing interests of PKA phosphorylation of cardiac troponin I and strong crossbridge on The authors declare no competing or financial interests. conformational transitions of the N-domain of cardiac troponin C in regulated thin filaments. Biochemistry 46, 9752-9761. Dorn, G. W.II. (2007). The fuzzy logic of physiological cardiac hypertrophy. Funding Hypertension 49, 962-970. A.N.K. is supported by a Doctoral Training Partnership from the Biotechnology and Dorn, G. W., II, Robbins, J. and Sugden, P. H. (2003). Phenotyping hypertrophy: Biological Sciences Research Council (BBSRC). J.M.K. is supported by a Post eschew obfuscation. Circ. Res. 92, 1171-1175. Doctoral Fellowship from the Heart and Stroke Foundation of Canada. T.E.G. is Driedzic, W. R. and Gesser, H. (1994). 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