From Molecular Interactions to Whole Muscle Strength: connecting small-scale interactions to muscle fiber function through mathematics

Muscle contraction is an essential biological process than spans physiological size scales, ranging from molecular interactions between the proteins actin and myosin, to larger cellular behavior, and ultimately whole-muscle function. The mechanisms of contraction are intriguing to study because unique behavior occurs at each physiological size scale. Developing a detailed understanding of the connections across scales is particularly important, because whole-muscle dysfunction and disease are often attributed to small-scale mutations. Thus, a multi-scale model of contraction is necessary to form a comprehensive understanding of muscle function. In the following dissertation, I develop a multi-scale model of muscle contraction based in well-measured molecular mechanisms that spans physiological size scales to connect to the larger fiber level. In each chapter, I focus on an unexplained attribute of muscle contraction, and using biophysical modeling and quantitative techniques, I extend the theory to describe experimental measurements across scales.In Chapter 1, I begin by providing an overview of the literature of muscle contraction to contextualize my research within the broader field. In Chapter 2, I explore muscle fatigue, and through development of a model to describe molecular measurements under the fatiguing conditions of acidosis and increased phosphate, provide novel insight into a molecular basis for contractile fatigue. In Chapter 3, I scale molecular interactions to the cellular level to explore the mechanisms behind the force transient response of a muscle fiber after a small, rapid stretch. By adjusting the model to replicate force transient measurements, I suggest a mechanism for unexplained fiber phenomenon, and highlight the complex connection between molecular kinetics and fiber-level behavior. In Chapter 4, I investigate the regime of large-amplitude, rapid lengthening of muscle fibers. To develop the model to describe these measurements, I extend my modeling framework to explicitly model multiple-sarcomere systems, and illustrate the need for such a model in capturing the effects of sarcomere instabilities that arise during rapid large-amplitude lengthening. Taken together, the work presented in the following chapters seeks to deepen our knowledge of muscle contraction. By developing mathematical models to describe unknown muscle behaviors, we make connections across physiological size scales and provide insight into molecular mechanisms that cause whole-muscle function, ultimately working towards a comprehensive theory of muscle