Autocrine Action of Elevated FGF-21 Contributing to Skeletal Muscle Atrophy in Response to Mitochondrial Dysfunction

点击翻译按钮获取中文摘要

PROJECT SUMMARY Skeletal muscle atrophy and muscle wasting is associated with both acute and chronic pathological conditions such as traumatic spinal cord injury and inpatient bedrest. Decreases in muscle mass from the atrophy is associated with power outcomes to other comorbidities, and increased susceptibility to obesity and diabetes. Current pharmaceutical interventions to increase muscle mass have been limited in their effectiveness. This poor efficacy is in part due to the limited understanding of the different mechanisms that contribute to decrease muscle mass. Mitochondrial dysfunction has been proposed as one of the contributors to skeletal muscle atrophy. However, the precise mechanisms that contribute to impaired mitochondrial functionality and the development of skeletal muscle atrophy is unknown. Mitochondrial dynamics have emerged as key regulators of both physiology and pathology in skeletal muscle. We have recently reported that induced adult skeletal muscle deletion of both mitofusin 1 and 2 have a profound effect on exercise capacity. Furthermore, preliminary analysis of these animals exhibit signs of decrease muscle mass and the induction of the unfolded protein response (UPR) and atrophy genes. We also observed elevated levels of FGF21 in skeletal muscle and circulation. These data suggest that adult skeletal muscle mitochondrial dysfunction and elevated muscle-derived FGF21 contributes to the development of muscle atrophy. Furthermore, utilizing a spinal cord injury (SCI) model, which develops pathological skeletal muscle atrophy, we observe elevated levels of skeletal muscle Fgf21 mRNA. We hypothesize that the observed elevated skeletal muscle derived FGF21 in circulation further contributes to the observed atrophy. Therefore, the overall objective of this proposal is to understand the contribution of mitochondrial dysfunction in skeletal muscle to the development of skeletal muscle atrophy. Using genetic models and translatable therapeutic interventions we will attempt to address this very important question. Results from this proposal have broad implications for our understanding of the molecular changes that contribute to the development of skeletal muscle atrophy. The specific aims are to: 1.) Establish the requirement of FGF21 signaling for skeletal muscle atrophy in response to muscle mitochondrial dysfunction; 2.) Reveal the contribution of elevated FGF21 in the development of skeletal muscle atrophy in response to a contusion spinal cord injury (SCI); 3.) Determine whether pharmacologic inhibition of FGF21 signaling after spinal cord injury (SCI) prevents skeletal muscle atrophy. This proposal will to provide much needed insights into our understanding of molecular pathogenesis of skeletal muscle atrophy.