Myosin-Binding Protein C Stabilizes, But Is Not the Sole Determinant of SRX Myosin in Cardiac Muscle
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AbstractThe myosin Super Relaxed (SRX) state is central to striated muscle metabolic and functional regulation. In skeletal muscle, SRX myosin are predominantly colocalized with Myosin-Binding Protein C (MyBP-C) in the C-zone, proximal to the sarcomere center. To define how MyBP-C and its specific domains contribute to stabilizing the SRX state in cardiac muscle, we took advantage of transgenic MyBP-C null mice and those expressing MyBP-C with a 271 residue N-terminal truncation. Utilizing super-resolution microscopy, we determined the lifetime and sub-sarcomeric location of individual fluorescent-ATP turnover events within isolated cardiac myofibrils. The proportion of SRX myosin was highest in the C-zone (716%) and lower in the D-zone (4510%) which lies farther from the sarcomere center and lacks MyBP-C, suggesting a possible role for MyBP-C in stabilizing the SRX state within the C-zone. However, myofibrils from MyBP-C null mice demonstrated an ~40% SRX reduction, not only within the now MyBP-C-free C-zone (499% SRX), but also within the D-zone (225% SRX). These data suggest that the influence of MyBP-C on the SRX state is not limited to the C-zone, but extends along the thick filament. Interestingly, myofibrils with N-terminal truncated MyBP-C had an SRX content and spatial gradient similar to the MyBP-C null, indicating that the N terminus of cardiac MyBP-C is necessary for MyBP-Cs role in establishing SRX along the entire thick filament. Given that SRX myosin are enriched in the C-zone, even in the absence of MyBP-C or its N-terminus, an inherent bias must exist in the structure of the thick filament to stabilize the SRX state. One candidate may be a differential in the super repeats of titin that interact with MyBP-C and myosin and which template the thick filament.
