Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure.
| Autor: | Hessel AL; Institute of Physiology II, University of Muenster; Muenster, Germany., Kuehn M; Institute of Physiology II, University of Muenster; Muenster, Germany., Han SW; Institute of Physiology II, University of Muenster; Muenster, Germany., Ma W; BioCAT, Department of Biology, Illinois Institute of Technology; Chicago, USA., Irving TC; BioCAT, Department of Biology, Illinois Institute of Technology; Chicago, USA., Momb BA; Department of Kinesiology, University of Massachusetts - Amherst; Amherst, MA, USA., Song T; Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA., Sadayappan S; Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA., Linke WA; Institute of Physiology II, University of Muenster; Muenster, Germany., Palmer BM; Department of Molecular Physiology and Biophysics, University of Vermont; Burlington, VT, USA. |
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| Jazyk: | angličtina |
| Zdroj: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 23. Date of Electronic Publication: 2023 Oct 23. |
| DOI: | 10.1101/2023.10.19.563160 |
| Abstrakt: | 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. Competing Interests: Competing Interest Statement: TI provides consulting and collaborative research studies to Edgewise Therapeutics Inc. ALH and MK are owners of Accelerated Muscle Biotechnologies Consultants LLC, and SS provides consulting and collaborative research studies to the Leducq Foundation (CURE-PLAN), Red Saree Inc., Greater Cincinnati Tamil Sangam, Novo Nordisk, Pfizer, AavantiBio, Affinia Therapeutics Inc., Cardiocare Genetics - Cosmogene Skincare Pvt Ltd, AstraZeneca, MyoKardia, Merck and Amgen, but such work is unrelated to the content of this article. Other authors declare that they have no competing interests. |
| Databáze: | MEDLINE |
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