New Insights in the Role of Cardiac Myosin Binding Protein C As a Regulator of Cardiac Contractility

Abstract

See related article, pages 884–890 Myosin Binding Protein C is a large multidomain protein that is found in the A-band region of the sarcomere where it associates with the thick filament.1 Mutations in cardiac myosin binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy2 but the functions of cMyBP-C are not well resolved. In this issue Moss and colleagues (Stelzer et al3) provide important new insights in the role of cMyBP-C in the regulation of cardiac muscle contraction. A binding site for the light meromyosin (LMM) domain of myosin is found near the C-terminus of MyBP-C and a second site that binds the S2 domain of myosin is present near the N-terminus of MyBP-C.4 The cardiac MyBP-C isoform contains protein kinase A (PKA) phosphorylation sites within the S2 binding site that are absent in skeletal muscle isoforms. Although phosphorylating these residues abolishes binding to myosin S2,4 the functional role of this phosphorylation is not well understood. Stelzer et al3 examined the effect of PKA on stretch activation in skinned cardiac myocytes of wildtype and cMyBP-C KO mice. Their findings provide an important piece of the puzzle—cMyBP-C slows crossbridge cycling kinetics (confirming earlier results5) and, importantly, this effect can be relieved by PKA-based phosphorylation of cMyBP-C. It is well known from work initiated by Professor Pringle mid last century that stretch activation is most pronounced in asynchronous flight muscle, where it gives rise to wing beat frequencies that far exceed the capacity of the sarcoplasmic reticulum to activate and relax myofilaments.6 Although cardiac muscle largely relies on calcium cycling for activation and relaxation, several decades ago Steiger and colleagues7 and more recently Moss and colleagues8 have shown that stretch activation …