Myosin kinetics during shortening and lengthening in striated muscles

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Daily activities, such as walking up stairs or carrying a bag of groceries, muscles are constantly exposed to varying loads and levels of activation as different muscles shorten and lengthen. For nearly a century, studies have shown that muscles use energy differently during shortening versus lengthening. The studies supported by this research funding will test how whole-muscle characteristics of shortening and lengthening are linked to changes in the molecular activity of the motor protein, myosin. Fundamentally, myosin is the molecular motor that turn chemical energy into force and shortening in a muscle, thereby powering locomotion and blood flow. The goal of this proposal is to measure, model, and predict how myosin activity changes with muscle length during a contraction. There are three main types of striated muscle: slow skeletal muscle, fast skeletal muscle, and cardiac muscle. These muscle types have distinctly different functions, and a better mechanistic understanding of the molecular phenomena underlying force production and power output during muscle shortening and lengthening will ultimately help determine critical mechanisms of coupling from the molecule to the tissue and organism levels that enable movement. A portion of these research efforts will continue to train a diverse set of undergraduate and graduate students in biophysical and computational biology research. Outreach and educational efforts, in collaboration with the Native American Programs Office and Office of Undergraduate Research, will inform students at local schools and regional Tribal Colleges about the wide-ranging potential to integrate their scientific interests with fulfilling employment opportunities.In the proposed research, biophysical system analysis will be used to measure how dynamic changes in muscle length influence myosin kinetics and force generation. Measurements of myosin rate-transitions in intact, electrically stimulated skeletal and cardiac muscles will be extended to probe isometric contraction, as well as dynamic contractions during lengthening and shortening. Complementary skinned fiber measurements will enable measurements of cross-bridge nucleotide handling rates as muscle fibers shorten and lengthen. These empirical findings will be integrated with computational models of muscle contraction to better interpret and predict the impact of myosin force production and energy utilization from the molecule to the sarcomere, fiber, and muscle. This principled, quantitative approach will provide an initial step towards defining similarities and differences between striated muscle type, myosin isoform, and muscle structure that ultimately influence functional diversity of striated muscle systems.