Quantitative Bioengineering Analysis of Muscle Mechanics and Metabolism

Using the methods of engineering analysis, we have developed a computational platform that incorporates current knowledge of molecular structure, biochemical energetics, and actomyosin binding kinetics to describe muscle contraction. Developed comprehensive model can be used to (1) generate new mechanistic hypotheses concerning the functions of the contractile proteins myosin and actin and (2) quantitatively evaluate the roles of accessory and regulatory proteins in contraction.

This computational model is a powerful analytical and predictive tool in studies of muscle physiology in health and disease. Presently, no models of contraction account for complications due to both (1) extensibility of the actin and myosin filaments and (2) Ca2+ regulation of contraction. Filament extensibility results in non-uniform load transfer along the thick and thin filaments, which introduces variability in the stress and strain of the myosin heads during their interactions with actin. These effects must be taken into account to understand how cross-bridge forces affect chemical transitions in the actomyosin ATPase cycle and vice versa. Further, quantitative understanding of Ca2+ regulation will allow (1) more accurate predictions of the macroscopic mechanical and energetic consequences of specific regulatory events and (2) more accurate explanations of macroscopic events in terms of underlying molecular processes.

These problems are addressed via a multidisciplinary approach that spans engineering science, computational science, and biophysics and rests entirely upon first principles. The developed model integrates a critical missing element – filament extensibility – with recent advances in understanding the (1) biochemical states of myosin; (2) transitional rate constants in the actomyosin ATP hydrolysis cycle; (3) function of myosin molecular motors in the thick and thin filament lattice (sarcomere); and (4) Ca2+ regulation of myosin binding. The model combines either probabilistic or stochastic actomyosin binding kinetics with finite element analysis including spatially discrete sarcomere lattice consistent with the periodicities of the thick and thin filaments.

The developed computational model invokes unifying principles that apply to the actomyosin cycle regardless of muscle type and it has sufficient flexibility to account for contraction kinetics and regulation of contraction in different muscle types. Quantitative modeling of contraction is ultimately essential for understanding the molecular basis for a wide range of syndromes and diseases, such as airway narrowing in asthma and weakness of both heart and skeletal muscles in heart failure.