Novel roles for satellite cells in adult skeletal muscle adaptation

Abstract: Under the current award, we have acquired exciting new evidence that satellite cells are necessary for the proper remodeling of the extracellular matrix during hypertrophy. We reported that in muscle depleted of satellite cells there was a significant increase in fibrosis that was associated with a blunted hypertrophic response. We hypothesize that activated satellite cells are capable of repressing the synthesis of extracellular matrix components by fibroblasts through exosomal delivery of satellite cell-derived microRNAs. Thus, the loss of satellite cells removes this “brake” leading to the over-production of collagen and ultimately the observed fibrosis. A primary goal of this proposal is to test this model as well as determine if the increased fibrosis is responsible for limiting long-term hypertrophic growth. Finally, we have published data in humans that suggests, unlike fast-twitch fibers, hypertrophy of slow-twitch fibers may require satellite cells. The objectives of this proposal are to investigate these novel roles for satellite cells in skeletal muscle plasticity by pursuing the following aims. Aim 1 will determine if satellite cells are necessary for proper extracellular matrix remodeling during skeletal muscle hypertrophy. Aim 2 will determine if fibrosis attenuates long-term hypertrophy in satellite celldepleted muscle. Aim 3 will determine if there is a fiber-type specific requirement for satellite cells during skeletal muscle hypertrophy. Our published work and new preliminary data clearly show that our understanding of satellite cell function in adult skeletal muscle adaptation remains incomplete. The studies described in this proposal address this fundamental gap in our knowledge and are expected to provide critical information necessary to more effectively evaluate the use of satellite cells as a therapeutic agent to prevent or restore the loss of skeletal muscle mass associated with dystrophies, cancer, age and rehabilitation following disuse