Dynamics of cross-bridge cycling, ATP hydrolysis, force generation, and deformation in cardiac muscle. (July 2016)

• Record Type: Journal Article
• Authors: Tewari, Shivendra G.; Bugenhagen, Scott M.; Palmer, Bradley M.; Beard, Daniel A.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 96(2016:Jul.)
• Page Start: 11
• Page End: 25
• Publication Date: 2016-07
• Subjects: Cross-bridge cycle -- Viscoelasticity -- Cardiac muscle -- Force generation -- Metabolites -- Sinusoidal perturbation analysis; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.02.006
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Despite extensive study over the past six decades the coupling of chemical reaction and mechanical processes in muscle dynamics is not well understood. We lack a theoretical description of how chemical processes (metabolite binding, ATP hydrolysis) influence and are influenced by mechanical processes (deformation and force generation). To address this need, a mathematical model of the muscle cross-bridge (XB) cycle based on Huxley's sliding filament theory is developed that explicitly accounts for the chemical transformation events and the influence of strain on state transitions. The model is identified based on elastic and viscous moduli data from mouse and rat myocardial strips over a range of perturbation frequencies, and MgATP and inorganic phosphate (Pi) concentrations. Simulations of the identified model reproduce the observed effects of MgATP and MgADP on the rate of force development. Furthermore, simulations reveal that the rate of force re-development measured in slack–restretch experiments is not directly proportional to the rate of XB cycling. For these experiments, the model predicts that the observed increase in the rate of force generation with increased Pi concentration is due to inhibition of cycle turnover by Pi. Finally, the model captures the observed phenomena of force yielding suggesting that it is a result of rapid detachment of stretched attached myosin heads. Highlights: A new kinetic–dynamic model of muscle contraction is developed. The model describes apparent elastic and viscous properties of cardiac muscle. A synthesis for a number of previously observed phenomena is developed. The effects of [Pi] in slack–restretch experiments are elucidated. The phenomenon of force yielding during muscle lengthening is elucidated.