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PERSPECTIVES |
Departments of
1 Anaesthesia and Critical Care Medicine
2 Pediatrics, Johns Hopkins University, Ross Building Room 1144, 720 Rutland Avenue, Baltimore, MD 21205, USA
Email: murphy{at}jhmi.edu
In both cardiac and skeletal muscles, contraction begins when Ca2+ binds to a regulatory site or sites in the N-lobe of troponin (Tn) C. Ca2+ binding to TnC induces sequential protein–protein interactions between TnC and TnI, TnI and TnT, and TnI–TnT and tropomyosin (Tm). As a result, Tm moves along actin (A) molecules exposing the sites for myosin S1 to attach thus leading to contraction. Recent protein biochemical, protein crystal structural, and cell physiology studies have advanced our understanding of the structure and function of myofilament proteins, especially the thin filament proteins (reviewed in Gordon et al. 2000; Kobayashi & Solaro, 2005). It has been demonstrated that for each seven actin monomers, there is one Tm and one Tn (7: 1: 1, A: Tm: Tn), which makes up one regulatory unit (RU). This structural arrangement forms the basis for cooperative interactions not only between Tn–Tm along the thin filament within the unit but also cooperative interactions between near-neighbouring regulatory units when cross-bridges are formed. In fact, it has been hypothesized that 12–14 actin monomers are controlled by one Tn. This hypothesis has recently been supported by Regnier et al. (2002) who have shown that in skeletal muscle, Ca2+-triggered activation of thin filament spread beyond the regulatory unit up to 10–12 actins which compose one functional unit (FU).
What about cardiac muscle activation? The sequential events after Ca2+ binding to TnC are very similar in both types of muscles. However, several lines of evidence may indicate that cardiac muscle activates in a unique fashion. (1) The Ca2+ transient during systole may not be long enough to fully activate the thin filament. (2) Cardiac muscle must have a greater sarcomere length dependence of force development due to the narrow range of sarcomere lengths the heart normally works. (3) Cardiac muscle is more responsive to neuro/hormonal stimulation. In this issue of The Journal of Physiology, Gillis et al. (2007) have demonstrated that a cardiac FU in thin filament activation is limited within a RU in that Tn activates 
7 actins upon Ca2+ activation, and that the behaviour of the cardiac FU depends on bound cross-bridges within the RU and is relatively independent of near-neighbour FUs (i.e. greater local control of activation). Although the molecular mechanism for the local control of thin filament activation is not precisely known, these findings indeed highlight the fact that different isoforms of regulatory proteins may be responsible for the differences in thin filament activation between cardiac and fast skeletal muscles. For example, as discussed by Gillis et al. structural and kinetic differences in Ca2+ binding to cTnC, cTnI–cTnC interactions between fast skeletal and cardiac isoforms, as well as more flexible Tm in cardiac muscle could contribute to the differences in RUs between skeletal and cardiac muscle.
The findings that cardiac muscle activation is more limited within the RU and has a greater reliance on crossbridge attachment, thus allowing greater and finer local control of activation and force generation, has important implications for pathophysiological states. For example, hypertrophic and dilated cardiomyopathies can be caused by mutations in genes which encode thick or thin filament proteins (Morita et al. 2005). These mutant proteins impact on Ca2+ sensitivity, sarcomere length dependence and also cross-bridge behaviour of the cardiac muscle. Post-translational modifications also impact on thin filament proteins in disease states including degradation and oxidation of myofilament proteins in ischaemia/reperfusion injury which are functionally significant. Finally, cardiac muscle activation is influenced by neuro/hormonal modulation via protein kinase signalling pathways. In heart failure, altered phosphorylation of myofilament proteins may alter cross-bridge dynamics and decrease force production.
Precisely how of each of the myofilament proteins contribute to the limited near-neighbour interactions and greater cross-bridge attachment control of activation in cardiac muscle is not known and should be the focus of future investigations. Understanding the molecular properties of these regulatory proteins will no doubt help us to better appreciate the nature of cardiac contraction at both whole organ and cellular level in health and disease.
References
Gillis TE, Martyn DA, Rivera AJ & Regnier M (2007). Investigation of thin filament near-neighbour regulatory unit interactions during force development in rat skinned cardiac muscle. J Physiol 580, 561–576.
Gordon AM, Homsher E & Regnier M (2000). Regulation of contraction in striated muscle. Physiol Rev 80, 853–924.
Kobayashi T & Solaro RJ (2005). Calcium, thin filaments, and the integrative biology of cardiac contractility. Annu Rev Physiol 67, 39–67.[CrossRef][Medline]
Morita H, Seidman J & Seidman CE (2005). Genetic causes of human heart failure. J Clin Invest 115, 518–526.[CrossRef][Medline]
Regnier M, Rivera AJ, Wang CK, Bates MA, Chase PB & Gordon AM (2002). Thin filament near-neighbour regulatory unit interactions affect rabbit skeletal muscle steady-state force–Ca2+ relations. J Physiol 540, 485–497.
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