Regulation of Skeletal Muscle Mitochondrial Quality Control Parameters and Systemic Metabolism

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PROJECT SUMMARY Obesity and type II diabetes (T2D) is associated with skeletal muscle mitochondrial dysfunction. Current pharmaceutical interventions have been limited in their ability to restore normal mitochondrial function, in part due to limited therapeutic targets. To date, exercise is the best-known treatment for many of these metabolic diseases. The positive effects of exercise are largely considered to be the result of both the quality control and functionality of mitochondria. However, the molecular pathways regulating mitochondria quality control is not fully understood. Members of the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators have been identified as being important to mitochondria and ultimately muscle function. The PGC-1α isoform has been credited with being the family member responsible for most, if not all, of beneficial changes in response to exercise. However, we observed that deletion of PGC-1α in skeletal muscle does not affect the adaptive changes in mitochondrial parameters. Moreover, we have also shown that simultaneously deleting both PGC-1α and PGC-1β in skeletal muscle have profound effect on mitochondrial function, but not mitochondrial content suggesting differences in mitochondrial quality control parameters. These data suggest that other players are involved in the regulation of mitochondrial function and number in skeletal muscle. We are confident that the much-understudied family member PGC-1 related coactivator (PRC) is this factor. In addition, the role PRC plays in skeletal muscle is unknown. Furthermore, the observation that PRC is induced in response to exercise and that whole body heterozygote for PRC deletion have a metabolic dysfunction, suggests strongly it plays a role in the exercise response. Therefore, the overall objective of this proposal is to understand the role PRC plays in skeletal muscle with regards to mitochondrial quality control and whole-body systemic metabolism. Using genetic models, diet induced and exercise paradigms, cell-based and mitochondrial assays we will attempt to address this very important question. Results from this proposal have broad implications for our understanding of metabolic disorders in skeletal muscle as well as the role of PRC in skeletal muscle. The specific aims are to: 1.) to define the role of PRC in skeletal muscle mitochondrial quality control, both during baseline and exercise training; 2.) to interrogate the effect of diet-induced metabolic imbalance on mitochondrial quality control in adult skeletal muscle with acquired mitochondrial oxidative capacity deficiency; and 3.) to demonstrate that exercise training preserves mitochondrial quality control in adult skeletal muscle with impaired oxidative capacity. This proposal will to provide much needed insights into our understanding of PRC in skeletal muscle and its contribution to metabolic dysfunction.