NSF Award
2217246
Muscles provide the primary means for animals to produce force, move, and interact with their environment. Muscle function is a consequence of hierarchical structure from molecular to whole muscle and muscle/skeletal systems. However, deep understanding of how muscles work is limited by research that does not fully cross these scales. Multiscale studies that investigate how genes encode proteins, how trillions of proteins of different kinds interact, how muscle mass and shape influence contraction, and how skeletal geometry tunes the speed and forcefulness of movements are the best avenue for enabling new insights into muscle performance. This project leverages the synergy of state-of-the-art, multiscale experimental techniques, and mathematical modeling of muscle, to understand bite performance in rodent models. Rodents have a range of bite strategies, jaw geometries, and muscle protein compositions, including a unique type of the muscle motor-protein myosin called masticatory myosin. Previous studies have suggested that masticatory myosin has exceptional properties that could provide new insights into how muscles produce bite forces. This project will test whether bite performance is influenced primarily by muscle size and shape, skeletal geometry, or the presence of masticatory myosin. Insights gathered from this integrative complement of studies will inform future studies of how muscle function is controlled by features of muscle tissue. In the broader impact activities of this project, the principle that biological function is “more than the sum of its parts” will be introduced through a custom-coded computer game that will teach secondary school students from groups underrepresented in STEM about how muscles function.<br/><br/>Understanding complex biological systems like muscle is challenging without multiscale convergence approaches, such as those used in this project. A fundamental idea in muscle physiology is the trade-off between force and velocity. However, a masticatory isoform of the myoprotein myosin has been suggested to be both forceful and fast. Unique mechanochemistry of two molecular loop sequences connecting myosin functional domains could explain this paradoxical phenomenon. This idea will be tested using targeted mutagenesis of C2C12 muscle cells, in-vitro motility assays, and single-fiber experiments that measure peak and loaded velocity of diverse myosin aggregates. An alternate idea is that fast and strong performance of jaw muscles with masticatory myosin is due to organ- to organism-scale differences in muscle size, geometry, bite type, and biomechanics that can buffer myosin force or speed limitations. This idea will be tested in experiments where muscle activation, strain, force, and leverage dynamics are measured using electromyography, sonomicrometry, micro force-buckles, and X-ray Reconstruction of Moving Morphology during biting on food items with controlled size and varying hardness. These methods will permit determination of the realized force-velocity of biting. Rodents are ideal for determining the cross-scale mechanistic bases of force-velocity modulation, as phenotypes exist with distinct myosin isoform expression but shared bite biomechanics. Force-velocity relationships across biological scales (actomyosin, myofibers, intact muscles, and whole feeding systems) will be coupled using a subtractive approach, and multiscale mathematical muscle modeling will be used to determine the mechanistic bases for emergent performance in geometrically similar or different rodents that either possess or lack masticatory myosin.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
