title: Molecular determinants of force production in human skeletal muscle fibers: effects of myosin isoform expression and cross-sectional area.
abstract: Skeletal muscle contractile performance is governed by the properties of its constituent fibers, which are, in turn, determined by the molecular interactions of the myofilament proteins. To define the molecular determinants of contractile function in humans, we measured myofilament mechanics during maximal Ca(2+)-activated and passive isometric conditions in single muscle fibers with homogenous (I and IIA) and mixed (I/IIA and IIA/X) myosin heavy chain (MHC) isoforms from healthy, young adult male (n = 5) and female (n = 7) volunteers. Fibers containing only MHC II isoforms (IIA and IIA/X) produced higher maximal Ca(2+)-activated forces over the range of cross-sectional areas (CSAs) examined than MHC I fibers, resulting in higher (24-42%) specific forces. The number and/or stiffness of the strongly bound myosin-actin cross bridges increased in the higher force-producing MHC II isoforms and, in all isoforms, better predicted force than CSA. In men and women, cross-bridge kinetics, in terms of myosin attachment time and rate of myosin force production, were independent of CSA, although women had faster (7-15%) kinetics. The relative proportion of cross bridges and/or their stiffness was reduced as fiber size increased, causing a decline in specific force. Results from our examination of molecular mechanisms across the range of physiological CSAs explain the variation in specific force among the different fiber types in human skeletal muscle, which may have relevance to understanding how various physiological and pathophysiological conditions modulate single-fiber and whole muscle contractility.
authors.affiliation: Department of Molecular Physiology and Biophysics, College of Medicine, University of Vermont, Burlington, Vermont; Department of Kinesiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts markmiller@kin.umass.edu.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Miller
authors.affiliation: Department of Molecular Physiology and Biophysics, College of Medicine, University of Vermont, Burlington, Vermont;
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Bedrin
authors.affiliation: Department of Medicine, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Ades
authors.affiliation: Department of Molecular Physiology and Biophysics, College of Medicine, University of Vermont, Burlington, Vermont;
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Palmer
authors.affiliation: Department of Molecular Physiology and Biophysics, College of Medicine, University of Vermont, Burlington, Vermont; Department of Medicine, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Toth
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D053580:Muscle Strength; D009210:Myofibrils / Q000378:metabolism; D024461:Myosin Type I / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D020033:Protein Isoforms; D052097:Quadriceps Muscle / Q000166:cytology / Q000378:metabolism*; D012737:Sex Factors; D015398:Signal Transduction; D024744:Skeletal Muscle Myosins / Q000378:metabolism; D055815:Young Adult
chemical_list: D000199:Actins; C498718:MYO10 protein, human; D020033:Protein Isoforms; D024461:Myosin Type I; D024744:Skeletal Muscle Myosins; D009218:Myosins
keywords: cross bridge; mechanical properties; muscle fiber