Review focus series: sarcomeric proteins as key elements in integrated control of cardiac function

Abstract

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. Figure 1 Scheme summarizing signalling mechanisms controlling cardiac function. See text for further description. 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 …