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bioRxiv · 10.1101/2023.10.19.563160

Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure.

Hessel, A. L.·Kuehn, M.·Han, S.-W.·Ma, W.·Irving, T. C.·Momb, B. A.·Song, T.·Sadayappan, S.·Linke, W. A.·Palmer, B. M.
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Abstract

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, A. L., Kuehn, M., Han, S.-W., Ma, W., Irving, T. C., Momb, B. A., Song, T., Sadayappan, S., Linke, W. A., Palmer, B. M.. 2023-10-23. Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure.. https://doi.org/10.1101/2023.10.19.563160

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