Cardiovascular Research Advance Access originally published online on January 10, 2008
Cardiovascular Research 2008 77(4):616-618; doi:10.1093/cvr/cvn004
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Review focus series: sarcomeric proteins as key elements in integrated control of cardiac function
Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, College of Medicine, 835 S. Wolcott Avenue, Chicago, IL 60612, USA
* Corresponding author. Tel: +1 312 996 7620; fax: +1 312 996 1414. E-mail address: solarorj{at}uic.edu
Review and original articles in this focused issue of the Journal highlight the increased understanding of the role of sarcomeric proteins in control of cardiac function downstream of Ca2+ signalling. Figure 1 provides a context for integrating these articles in a minimal model of sarcomeric function in long- and short-term responses of the heart to stressors. In the model, state changes in the form of a physiological extrinsic stress, such as exercise or a pathophysiological stress such as hypertension promote a stream of mechanical and chemical signals, indicated as cytoskeletal, neurohormonal, and redox strains. Cytoskeletal strain induced by sarcomere length changes engage the Frank–Starling mechanism and also induce neurohormonal strains, as do feedback mechanisms. Readout of these neurohormonal signals is altered protein phosphorylation of cellular proteins including membrane proteins, transcription factors, and the sarcomeric proteins. Altered redox environment also induces post-translational modifications in sarcomeric proteins likely to trigger altered function independently of Ca2+ fluxes. Responses that compensate for the extrinsic stress maintain efficient cardiac function. For example, in exercise with increased venous return, rate and force of contraction and rate of relaxation are enhanced to match the increased heart rate and to permit cardiac output to increase with minimal increases in end-diastolic volume. A failure in the ability of the signalling cascade to engage compensatory pathways to maintain efficient function in response to an extrinsic stressor leads to decompensation and a viscous cycle ensues, exacerbating the stress.
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Emerging evidence has substantially altered the understanding of the relative significance of mechanisms at the level of cardiac sarcomeric proteins in the processes summarized in Figure 1. Sarcomeres are no longer viewed simply as generators of force and shortening. As indicated in Figure 1, sarcomeric proteins engage in the mechanical, neural, and hormonal signalling cascades that modify dynamics and intensity of the heart beat. An important concept developed in the review by Davis and Tikunova1 is evidence, indicating that the modulation of on- and off-rate constants of Ca2+ exchange with troponin C (TnC) is a factor in the control of the contraction relaxation cycle. These data add to existing concepts, which established a role for the modification of thick filament-related control of cross-bridge kinetics in power generation, and support the hypothesis that molecular mechanisms at the level of the thin filaments may be rate-limiting in contraction/relaxation. The data summarized by Hanft et al.2 also extend the generally accepted mechanism that the cellular basis of the Frank–Starling relation resides at the level of the sarcomeres.3 Hanft et al.2 review evidence supporting the idea that length-dependent activation of cardiac sarcomeres is not only a significant determinant of the relation between ventricular filling and ventricular pressure but also a variable controlled by signalling processes. Hanft et al.2 also emphasize the idea that late phases of ejection and isovolumic relaxation are governed by sarcomeric properties.
Neural and hormonal signals, which are indicated in Figure 1, induce altered phosphorylation of key sarcomeric proteins that modify myosin motor function or myofilament sensitivity to Ca2+ and are now recognized to be significant and rate-limiting processes in the heartbeat.4 Figure 1 indicates that a mechanism important in adaptation or maladaptation to the stress is in the levels of protein phosphorylation. In the case of sarcomeric proteins, there is evidence, indicated by the yin-yang symbol, that some phosphorylation events, e.g. myosin binding protein C and sites on TnI, promote cross-bridge kinetics and therefore cardiac power, whereas other sites on TnI and TnT depress cross-bridge kinetics.4 Linke5 reviews evidence that phosphorylation of titin modulates passive tension. We think that physiological states reflect a homeostatic distribution (adaptive phosphorylation) of these phosphorylated states, and pathophysiological states reflect a disturbance of this homeostasis with maladaptive distribution of these phosphorylations. Abundant evidence indicates that an inappropriate balance in protein phosphorylation is an important mechanism of maladaptive Ca2+ fluxes, heart rate, and conduction. In the case of the sarcomere in heart failure, the review by Hamdani et al.6 summarizes current data indicating that altered protein phosphorylation correlates with a depression in myofilament force development, an increase in sensitivity to Ca2+, and an increase in passive stiffness.
Sarcomeric proteins are not only downstream effectors of signalling cascades, but also transducers of many of these signals. Transcription factors and enzymes including kinases and phosphatases dock at sarcomeric sites. Mechanical and biochemical signals disengage these regulatory proteins, which then may move to other cellular sites. As presented elsewhere, this signal transduction function of the sarcomere permits remote control of actin–myosin interactions at the A-band function by signalling at the I–Z–I region.7 Linke's review5 focuses in detail on titin and also provides a discussion of how titin provides linkage among sarcomeric mechanosensing protein networks at the Z-disk, I-band, and M-band of the sarcomeres.
Figure 1 indicates that extrinsic stresses on the myocardium engage a process of cell growth, with cellular and chamber remodelling that may be adaptive as in the case of compensated hypertrophic growth of the heart with long-term exercise or increased afterload with hypertension. However, these processes may lead to decompensation, e.g. through maladaptive remodelling with isoform switching and altered expression of critical cellular and extracellular proteins. Intrinsic stressors in the form of mutations in cellular proteins linked to hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) also trigger growth and remodelling of the myocardium. Extensive data indicating that mutations in the sarcomeric proteins are the most common causes of HCM and DCM have provided strong evidence supporting the hypothesis that specific modifications in sarcomeric proteins are able to significantly affect cardiac function and trigger growth and remodelling.
The pursuit of mechanisms by which a mutation in a sarcomeric protein leads to cardiomyopathies is one of the most significant challenges in understanding inherited myocardial disorders. An original contribution by Iorga et al.8 tests the hypothesis that TnI mutations, most notably an HCM-linked mutation in the C-terminal mobile domain of cTnI, may regulate relaxation kinetics. They show that single myofibrils regulated by the mutant cTnI demonstrates no change in contraction kinetics, but a depression in relaxation kinetics and passive tension. Data reported by Revera et al.9 relate to the clinical significance of these diastolic abnormalities in carriers of an HCM-linked mutation in cTnT. Their study of pre-hypertrophic hearts of carriers emphasizes that relief of the diastolic abnormalities directly altering sarcomere Ca2+ sensitivity may prevent progression to decompensation. In his comprehensive review of sarcomeric mutations and inherited cardiomyopathies, Morimoto10 also describes data demonstrating in animal models that directly modifying sarcomeric sensitivity to Ca2+ may be an effective clinical approach to the treatment of familial dilated cardiomyopathies. Agents that directly affect sarcomeric function remain under active investigation.11 Moreover, it is significant that the data reported by Gopal et al.12 provide evidence that altered sarcomeric sensitivity to Ca2+ may be an important mechanism underlying the beneficial effects of clenbuterol, a β2-adrenergic receptor antagonist, in a model of heart failure.
Modifications in sarcomeric function may also be related to disturbances in myofibrillar assembly, a topic reviewed by Boateng and Goldspink.13 They summarize the complexity of processes by which sarcomeres are continually broken down and rebuilt. They also emphasize the technical challenges in understanding this critical process and point out novel aspects of the mechanism, including potential diurnal regulation by circadian proteins localized at the sarcomere. An original paper by Burgoyne et al.14 also deals with the theme of assembly with focus on the unique property of cardiac myofilaments in demonstrating variable lengths of thin filaments compared with vertebrate skeletal muscle.
In summary, reviews and original papers in this issue represent new directions in a field that has a long history. There is little doubt that investigators in the field of control of cardiac function are in for many surprises regarding the responsibilities of this organelle as a machine and as a centre of mechanical and biochemical signalling.
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Research in our laboratories is supported by grants from the National Institutes of Health [HL RO1 64035 (R.J.S.), HL RO1 22231 (R.J.S.), HL RO1 77195 (P.deT), RO1 HL 75494 (P.deT) and HL PO1 62426 (R.J.S. and P.deT.)] and from the American Heart Association.
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The opinions expressed in this article are not necessarily those of the Editors of the Cardiovascular Research or of the European Society of Cardiology.
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- Davis JP, Tikunova SB. Ca2+ exchange with troponin C and cardiac muscle dynamics. Cardiovasc Res (2008) 77:619–626.
[Abstract/Free Full Text] - Hanft LM, Korte SF, McDonald KS. Cardiac function and modulation of sarcomeric function by length. Cardiovasc Res (2008) 77:627–636.
[Abstract/Free Full Text] - Konhilas JP, Irving TC, de Tombe PP. Frank–Starling law of the heart and the cellular mechanisms of length-dependent activation. Pflugers Arch (2002) 445:305–310.[CrossRef][Web of Science][Medline]
- Solaro RJ, Wolska BM, Arteaga G, Martin AF, Buttrick P, de Tombe P. Modulation of thin filament activity in long and short term regulation of cardiac function. In: Molecular Control Mechanisms in Striated Muscle Contraction—Solaro RJ, Moss RL, eds. (2002) The Netherlands: Kluwer Academic Publishers. 291–327.
- Linke WA. Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc Res (2008) 77:637–648.
[Abstract/Free Full Text] - Hamdani N, Kooij V, van Dijk S, Merkus D, Paulus WJ, dos Remedios C, et al. Sarcomeric dysfunction in heart failure. Cardiovasc Res (2008) 77:649–658.
[Abstract/Free Full Text] - Solaro RJ. Remote control of A-band cardiac thin filament by the I-Z-I network of cardiac sarcomeres. Trends in Cardiovasc Med (2005) 15:148–152.[CrossRef]
- Iorga B, Blaudeck N, Solzin J, Neulen A, Stehle I, Lopez Davila AJ, et al. Lys184 deletion in troponin I impairs relaxation kinetics and induces hypercontractility in murine cardiac myofibrils. Cardiovasc Res (2008) 77:676–686.
[Abstract/Free Full Text] - Revera M, van der Merwe L, Heradien M, Goosen A, Corfield VA, Brink PA, et al. Troponin T and β-myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy. Cardiovasc Res (2008) 77:687–694.
[Abstract/Free Full Text] - Morimoto S. Sarcomeric proteins and inherited cardiomyopathies. Cardiovasc Res (2008) 77:659–666.
[Abstract/Free Full Text] - Kass DA, Solaro RJ. Mechanisms and use of calcium-sensitizing agents in the failing heart. Circulation (2006) 113:305–315.
[Free Full Text] - Gopal K.R., Soppa GKR, Lee J, Stagg MA, Felkin LE, Barton PJR, et al. Role and possible mechanisms of clenbuterol in enhancing reverse remodeling during mechanical unloading in murine heart failure. Cardiovasc Res (2008) 77:695–706.
[Abstract/Free Full Text] - Boateng SY, Goldspink PH. Assembly and maintenance of the sarcomere night and day. Cardiovasc Res (2008) 77:667–675.
[Abstract/Free Full Text] - Burgoyne T, Muhamad F, Luther PK. Visualization of cardiac muscle thin filaments and measurement of their lengths by electron tomography. Cardiovasc Res (2008) 77:707–712.
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