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Proc Natl Acad Sci U S A. 2019 Oct 7. pii: 201910549. doi: 10.1073/pnas.1910549116. [Epub ahead of print]

Skeletal MyBP-C isoforms tune the molecular contractility of divergent skeletal muscle systems.

Author information

Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405.
Cardiovascular Research Institute, University of Vermont, Burlington, VT 05405.
Discipline of Anatomy & Histology, School of Medical Sciences, The University of Sydney, Sydney, NSW 2006 Australia.
Australian Centre for Microscopy & Microanalysis, The University of Sydney, Sydney, NSW 2006 Australia.
Department of Physiological Science, Federal University of São Carlos, São Carlos, 13565-905 Brazil.
Heart, Lung and Vascular Institute, University of Cincinnati, Cincinnati, OH 45267.
Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267.
Department of Kinesiology and Physical Education, McGill University, Montreal, H2W 1S4 Canada.
Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405;


Skeletal muscle myosin-binding protein C (MyBP-C) is a myosin thick filament-associated protein, localized through its C terminus to distinct regions (C-zones) of the sarcomere. MyBP-C modulates muscle contractility, presumably through its N terminus extending from the thick filament and interacting with either the myosin head region and/or the actin thin filament. Two isoforms of MyBP-C (fast- and slow-type) are expressed in a muscle type-specific manner. Are the expression, localization, and Ca2+-dependent modulatory capacities of these isoforms different in fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles derived from Sprague-Dawley rats? By mass spectrometry, 4 MyBP-C isoforms (1 fast-type MyBP-C and 3 N-terminally spliced slow-type MyBP-C) were expressed in EDL, but only the 3 slow-type MyBP-C isoforms in SOL. Using EDL and SOL native thick filaments in which the MyBP-C stoichiometry and localization are preserved, native thin filament sliding over these thick filaments showed that, only in the C-zone, MyBP-C Ca2+ sensitizes the thin filament and slows thin filament velocity. These modulatory properties depended on MyBP-C's N terminus as N-terminal proteolysis attenuated MyBP-C's functional capacities. To determine each MyBP-C isoform's contribution to thin filament Ca2+ sensitization and slowing in the C-zone, we used a combination of in vitro motility assays using expressed recombinant N-terminal fragments and in silico mechanistic modeling. Our results suggest that each skeletal MyBP-C isoform's N terminus is functionally distinct and has modulatory capacities that depend on the muscle type in which they are expressed, providing the potential for molecular tuning of skeletal muscle performance through differential MyBP-C expression.


calcium regulation; in vitro motility; mass spectrometry; muscle contraction; myosin thick filament


Conflict of interest statement

Competing interest statement: S.S. provided consulting and collaborative research services to the Leducq Foundation, AstraZeneca, Merck, Amgen, and MyoKardia unrelated to the content of this manuscript.

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