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

Hessel, Anthony L.; Kuehn, Michel N.; Han, Seong-Won; Ma, Weikang; Irving, Thomas C.; Momb, Brent A.; Song, Taejeong; Sadayappan, Sakthivel; Linke, Wolfgang A.; Palmer, Bradley M.

doi:10.1038/s42003-024-06265-8

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

Journal Article · Mon May 27 00:00:00 EDT 2024 · Communications Biology

DOI:https://doi.org/10.1038/s42003-024-06265-8· OSTI ID:2470062

^[1]; Kuehn, Michel N. ^[1]; Han, Seong-Won ^[1]; ^[2]; Irving, Thomas C. ^[2]; Momb, Brent A. ^[3]; ^[4]; ^[4]; ^[1]; ^[5]

University of Muenster (Germany)
Illinois Institute of Technology, Chicago, IL (United States)
University of Massachusetts, Amherst, MA (United States)
University of Cincinnati, OH (United States)
University of Vermont, Burlington, VT (United States)

In striated muscle, the sarcomeric protein myosin-binding protein-C (MyBP-C) is bound to the myosin thick filament and is predicted to stabilize myosin heads in a docked position against the thick filament, which limits crossbridge formation. Here, we use the homozygous Mybpc2 knockout (C2^-/-) mouse line to remove the fast-isoform MyBP-C from fast skeletal muscle and then conduct mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2^-/- fibers present deficits in force production and calcium sensitivity. Structurally, passive C2^-/- fibers present altered sarcomere length-independent and -dependent regulation of myosin head conformations, with a shift of myosin heads towards actin. At shorter sarcomere lengths, the thin filament is axially extended in C2^-/-, which we hypothesize is due to increased numbers of low-level crossbridges. These findings provide testable mechanisms to explain the etiology of debilitating diseases associated with MyBP-C.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: German Research Foundation; National Institutes of Health (NIH); The American Heart Association; The PLN Foundation; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470062

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 7; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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