MUSC ADAP XRCS · Mechanisms of skeletal muscle adaptation to exercise and their implications in health and disease.

Sedentary lifestyles have led to the increase of obesity, type 2 diabetes, and sarcopenia (decreased muscle mass) of the elderly. Skeletal muscle plays a key role in these conditions, and it is clear that exercise can be as effective as medication in treating some of these ailments. The adaptation of muscle to exercise involves the coordinated regulation of gene networks, whose products adapt muscle function to new challenges (e.g. increased contractility or oxidative capacity). We have identified several novel members of the PGC-1 family of transcriptional coactivators, which is activated by exercise and has the ability to regulate important gene programs in muscle. By studying the function of these new coactivators, we hope to further elucidate the mechanisms by which muscle responds to exercise. Differences in conservation of certain functional protein domains indicate that specific PGC-1 forms might simultaneously regulate gene transcription and splicing. We propose that changes in alternative isoform expression may be part of the switch from sedentary to exercised muscle. We will characterize these processes by using RNA-sequencing since this technique provides information about transcript abundance and sequence. This analysis of muscle adaptation to exercise will allow us to understand how, in response to work, muscle can positively affect so many aspects of human health. This knowledge will help us design new therapeutic strategies to fight metabolic diseases.