Why the study?
The mechanism by which MyBP-C releases myosin heads into the ON state to facilitate crossbridge formation was unknown.
Does fast-isoform MyBP-C knockout alter mechanical function and myofilament structure in skeletal muscle?
Does fast-isoform MyBP-C knockout alter mechanical function and myofilament structure in skeletal muscle?
Knockout of fast-isoform MyBP-C in skeletal muscle alters myosin head regulation and myofilament structure, providing insights into the etiology of MyBP-C-associated diseases.
Does not yet inform clinical management of sarcomeric diseases; leaves open the mechanism by which MyBP-C activates myosin heads.
In striated muscle, some sarcomere proteins regulate crossbridge cycling by varying the propensity of myosin heads to interact with actin. Myosin-binding protein C (MyBP-C) is bound to the myosin thick filament and is predicted to interact and stabilize myosin heads in a docked position against the thick filament and limit crossbridge formation, the so-called OFF state. Via an unknown mechanism, MyBP-C is thought to release heads into the so-called ON state, where they are more likely to form crossbridges. To study this proposed mechanism, we used the C2 -/- mouse line to knock down fast-isoform MyBP-C completely and total MyBP-C by ∼24%, and conducted mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2 −/− fibers presented deficits in force production and reduced calcium sensitivity. Structurally, passive C2 -/- fibers presented altered SL-independent and SL-dependent regulation of myosin head ON/OFF states, with a shift of myosin heads towards the ON state. Unexpectedly, at shorter sarcomere lengths, the thin filament was axially extended in C2 -/- vs. non-transgenic controls, which we postulate is due to increased low-level crossbridge formation arising from relatively more ON myosins in the passive muscle that elongates the thin filament. The downstream effect of increasing crossbridge formation in a passive muscle on contraction performance is not known. Such widespread structural changes to sarcomere proteins provide testable mechanisms to explain the etiology of debilitating MyBP-C-associated diseases.
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Hessel et al. (2023) studied this question.
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