Muscle force emerges from dynamic actin-myosin networks, not from independent force generators.

Abstract

MUSCLE CELL BIOLOGY AND CELL MOTILITYMuscle force emerges from dynamic actin-myosin networks, not from independent force generatorsJosh E. BakerJosh E. BakerPublished Online:01 Jun 2003https://doi.org/10.1152/ajpcell.00597.2002MoreSectionsPDF (38 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat To the Editor: The data and analysis presented by Karatzaferi et al. (6) support a new paradigm for muscle contraction, which if correct demands a fundamental reassessment of decades' worth of muscle mechanics studies. At issue is how mechanics and chemistry are coupled in muscle.The conventional model of the past 40 years (4, 5) has mechanics and chemistry coupled within individual cross bridges, with ATP, ADP, and Pi concentrations formally expressed as functions of a mechanical parameter (the molecular strain,x) of an isolated cross bridge. In contrast, by expressing [ADP] as a function of a mechanical parameter of the muscle system (the macroscopic muscle force, PSL-ADP), Eq. 1in Karatzaferi et al. implicitly couples mechanics and chemistry at the level of an ensemble of cross bridges. Equations of this form have been legitimized only within the context of a thermodynamic muscle model (2, 3): a model originally developed to account for the first direct measurements of mechanochemical coupling in muscle (1). By demonstrating that Eq. 1 accurately describes their data, where conventional models fail, Karatzaferi et al. provide additional experimental support for a thermodynamic muscle model (2), not, as stated, “a molecular explanation for [it]”.The conventional model of mechanochemical coupling uses rational mechanics to describe muscle force as a sum of well-defined myosin cross-bridge forces. In contrast, a thermodynamic model describes muscle force as an emergent property of a dynamic actin-myosin network, within which the force of a given cross bridge stochastically fluctuates due to force-generating transitions of neighboring cross bridges that are transmitted through compliant linkages. The “molecular explanation” for a thermodynamic muscle model is that, through these intermolecular interactions, the mechanics and chemistry of a given cross bridge are mixed up with the mechanics and chemistry of its neighbors.The above competing descriptions of muscle force (molecular reductionist vs. thermodynamic) are mutually exclusive. As Gibbs points out, “If we wish to find in rational mechanics an a priori foundation for the principles of thermodynamics, we must seek mechanical definitions of temperature and entropy” (3a). Thus the thermodynamic muscle model (2, 3) supported by Karatzaferi et al. represents a fundamental shift in our understanding of muscle mechanics. In essence, if this model is correct, then one must conclude that the successes of conventional muscle models are superficial, resulting from strain (x)-dependent rate constants that were artificially tuned to make individual myosin cross bridges mimic the emergent properties (P) of dynamic actin-myosin networks in muscle. Although it remains to be determined which model most accurately describes muscle mechanics, growing support for a thermodynamic model of muscle (2, 3) from studies like that presented in Karatzaferi et al. suggests that this paradigm shift and its profound implications for our understanding of muscle contraction warrant careful consideration.REFERENCES1 Baker JE, LaConte LE, Brust-Mascher II, Thomas DD.Mechanochemical coupling in spin-labeled, active, isometric muscle.Biophys J77199926572664Crossref | PubMed | ISI | Google Scholar2 Baker JE, Thomas DD.A thermodynamic muscle model and a chemical basis for A. V. Hill's muscle equation.J Muscle Res Cell Motil212000335344Crossref | PubMed | ISI | Google Scholar3 Baker JE, Thomas DD.Thermodynamics and kinetics of a molecular motor ensemble.Biophys J79200017311736Crossref | PubMed | ISI | Google Scholar3a Gibbs JW.Elementary Principles in Statistical Mechanics.1902165Yale University PressNew Haven, CTGoogle Scholar4 Hill TL.Theoretical formalism for the sliding filament model of contraction of striated muscle. Part I.Prog Biophys Mol Biol281974267340Crossref | PubMed | Google Scholar5 Huxley AF.Muscle structure and theories of contraction.Prog Biophys71957255317ISI | Google Scholar6 Karatzaferi C, Myburgh KH, Chinn MK, Franks-Skiba K, Cooke R.The effect of an ADP analog on isometric force and ATPase activity of active muscle fibers.Am J Physiol Cell Physiol2842002C816C825Link | ISI | Google ScholarajpcellajpcellAJPCELLAmerican Journal of Physiology-Cell PhysiologyAm J Physiol Cell Physiol1522-15630363-6143American Physiological SocietyBethesda, MDajpcellajpcellAJPCELLAmerican Journal of Physiology-Cell PhysiologyAm J Physiol Cell Physiol1522-15630363-6143American Physiological SocietyBethesda, MD10.1152/ajpcell.00597.2002MUSCLE CELL BIOLOGY AND CELL MOTILITY Roger Cooke, and Christina Karatzaferi 1 Department of Biochemistry and Biophysics 2 Cardiovascular Research Institute 3 University of California 4 San Francisco, CA 94143 5 E-mail: [email protected]ucsf.edu 1620032846C1678C1679Copyright © 2003 the American Physiological Society200310.1152/ajpcell.00597.2002MUSCLE CELL BIOLOGY AND CELL MOTILITY 1620032846C1678C1679Copyright © 2003 the American Physiological Society2003REPLY To the Editor: We agree that our model provides support for the approach taken by Baker and colleagues. Reversal of the power stroke of a single myosin head would require the input of energy required by other heads and transmitted through the filament network. In this way, the properties of the muscle are the result of a collection of interacting motors. These conclusions arise from the fit of a model to the data. More direct experimental proof of this concept would be helpful. The following is an abstract of the article discussed in the subsequent letter: Karatzaferi, Christina, Kathryn H. Myburgh, Marc K. Chinn, Kathleen Franks-Skiba, and Roger Cooke. Effect of an ADP analog on isometric force and ATPase activity of active muscle fibers. Am J Physiol 284: C816–C825, 2003.—The role played by ADP in modulating cross-bridge function has been difficult to study, because it is hard to buffer ADP concentration in skinned muscle preparations. To solve this, we used an analog of ADP, spin-labeled ADP (SL-ADP). SL-ADP binds tightly to myosin but is a very poor substrate for creatine kinase or pyruvate kinase. Thus ATP can be regenerated, allowing well-defined concentrations of both ATP and SL-ADP. We measured isometric ATPase rate and isometric tension as a function of both [SL-ADP], 0.1–2 mM, and [ATP], 0.05–0.5 mM, in skinned rabbit psoas muscle, simulating fresh or fatigued states. Saturating levels of SL-ADP increased isometric tension (by P′), the absolute value of P′ being nearly constant, ∼0.04 N/mm2, in variable ATP levels, pH 7. Tension decreased (50–60%) at pH 6, but upon addition of SL-ADP, P′ was still ∼0.04 N/mm2. The ATPase was inhibited competitively by SL-ADP with an inhibition constant, K i, of ∼240 and 280 μM at pH 7 and 6, respectively. Isometric force and ATPase activity could both be fit by a simple model of cross-bridge kinetics. Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByModulators of actin-myosin dissociation: basis for muscle type functional differences during fatigueChristina Karatzaferi, Nancy Adamek, and Michael A. Geeves8 December 2017 | American Journal of Physiology-Cell Physiology, Vol. 313, No. 6 More from this issue > Volume 284Issue 6June 2003Pages C1678-C1679 Copyright & PermissionsCopyright © 2003 the American Physiological Societyhttps://doi.org/10.1152/ajpcell.00597.2002PubMed12734115History Published online 1 June 2003 Published in print 1 June 2003 Metrics