Muscle extracellular matrix, the connective tissue surrounding muscle fibers, has been shown to change with age, disuse, and neuromuscular disease. These conditions cause muscle fibrosis-a pathological increase in muscle extra cellular matrix. This work aims to understand the basic functional implications of muscle fibrosis at the level of tissues, organs and whole organisms. In addition to examining the mechanics of the system at various levels of biological organization, the project will combine complementary modeling and experimental approaches to better understand the fundamental properties of fibrotic muscle. The broad scientific goal is to elucidate the implications of fibrosis for muscle function, and to examine how such changes relate to deficiencies in gait and movement. In addition, outreach efforts will broaden research experiences for underrepresented groups and aid in the development of interdisciplinary lesson plans in high-school science curricula.
The extracellular matrix (ECM) of skeletal muscle is known to play a critical role in the passive elasticity and stiffness of muscle fibers and fascicles, but it remains unclear how variation in the properties of the ECM are likely to affect contractile performance, in vivo function, and gait. The project will integrate empirical studies using a well-established animal model system for aging (F344xBN rats) with modeling approaches to examine how the remodeling of the ECM impacts performance. The first objective will be to use isolated muscle fascicles and laser diffraction to characterize how age-related fibrosis alters the capacity of muscle fibers to produce mechanical work. The hypothesis is that increased ECM stiffness limits a muscle's ability to perform mechanical work by limiting radial expansion of muscle fibers and fascicles. The second objective is to use high-speed x-ray imaging to examine how muscle fibrosis affects muscle performance during normal locomotion. The project will test the hypothesis that increased muscle stiffness restricts muscle to operate at relatively short lengths, resulting in decreased force production in vivo. Finally, an examination of the effects of increasing passive stiffness on gait mechanics. Using empirical data from rats to drive forward dynamic gait simulations, the PIs will explicitly link the isolated effects of passive muscle stiffness on joint mechanics and whole-body performance. By integrating empirical studies of tissues, organs and whole organisms with model simulations the work will elucidate how variation in ECM properties affects performance across levels of biological organization.
