Structural OFF/ON transitions of myosin in relaxed porcine myocardium predict calcium-activated force

Ma, Weikang; McMillen, Timothy S.; Childers, Matthew Carter; Gong, Henry; Regnier, Michael; Irving, Thomas

doi:10.1073/pnas.2207615120

Structural OFF/ON transitions of myosin in relaxed porcine myocardium predict calcium-activated force

Journal Article · Wed Jan 25 00:00:00 EST 2023 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2207615120· OSTI ID:2423651

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Illinois Institute of Technology, Chicago, IL (United States)
Univ. of Washington, Seattle, WA (United States)

Contraction in striated muscle is initiated by calcium binding to troponin complexes, but it is now understood that dynamic transition of myosin between resting, ordered OFF states on thick filaments and active, disordered ON states that can bind to thin filaments is critical in regulating muscle contractility. These structural OFF to ON transitions of myosin are widely assumed to correspond to transitions from the biochemically defined, energy-sparing, super-relaxed (SRX) state to the higher ATPase disordered-relaxed (DRX) state. Here, in this study, we examined the effect of 2’-deoxy-ATP (dATP), a naturally occurring energy substrate for myosin, on the structural OFF to ON transitions of myosin motors in porcine cardiac muscle thick filaments. Small-angle X-ray diffraction revealed that titrating dATP in relaxation solutions progressively moves the myosin heads from ordered OFF states on the thick filament backbone to disordered ON states closer to thin filaments. Importantly, we found that the structural OFF to ON transitions are not equivalent to the biochemically defined SRX to DRX transitions and that the dATP-induced structural OFF to ON transitions of myosin motors in relaxed muscle are strongly correlated with submaximal force augmentation by dATP. These results indicate that structural OFF to ON transitions of myosin in relaxed muscle can predict the level of force attained in calcium-activated cardiac muscle. Computational modeling and stiffness measurements suggest a final step in the OFF to ON transition may involve a subset of DRX myosins that form weakly bound cross-bridges prior to becoming active force-producing cross-bridges.

View Accepted Manuscript (DOE)

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

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423651

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 5 Vol. 120; ISSN 1091-6490; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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Structural OFF/ON transitions of myosin in relaxed porcine myocardium predict calcium-activated force

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