Muscle function is essential for motion, exercise, and shivering, whereas physical inactivity is causally related to reduced metabolic fitness in animal models and humans. A critical requirement for muscle function is that proteins are properly produced and, if necessary, degraded to adapt the proteome to meet metabolic demands. However, there is a fundamental, open gap in understanding how challenges to muscle proteostasis are sensed and how protein fate is subsequently adapted to enhance muscle function in exercise or, conversely, how it is compromised in obesity. I hypothesize that protein fate is highly adaptive and can be fine-tuned to promote proteostasis, the integrity of muscle cells, and metabolic health. Identifying novel key regulators of these mechanisms in muscle may hold great therapeutic promise for targeting metabolic fitness to combat obesity and associated disorders. In this innovative project I want to define new mechanisms of muscle adaptation in humans and preclinical mouse models, with the ultimate goal of using this knowledge to improve muscle function and fitness in obesity. I will identify exercise- and obesity-specific substrates of the proteasome by ubiquitomics in human and mouse muscle and define how the ubiquitination and turnover of these proteins dictates muscle cell function. In a complementary approach, I will use novel loss- and gain-of-function mouse models allowing for precise muscle-specific manipulation of Nfe2l1, an adaptive regulator of proteasomal protein degradation, to define the biological and therapeutic significance of this pathway for muscle function in exercise and obesity. In summary, this novel work will provide a transformative molecular understanding of muscle adaption to metabolic challenges and provide insight into how this translates into metabolic fitness and the development of obesity and associated disorders in humans.
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