Grant: Project Grant

Skeletal muscles comprise a large proportion of body mass and are significant reserves of the body's energy substrates. The size and function of skeletal muscles are determined by the degree of protein synthesis and protein degradation. We performed preliminary experiments to identify novel genes that may regulate skeletal muscle size and function and identified a poorly characterized gene Depp1 (also known as C10orf10 in humans). Our experiments revealed that Depp1 protein is present inside the peroxisomes and mitochondria in normal skeletal muscles. Peroxisomes are organelles inside the cells that are important for degrading fat but in the process of this degradation, they produce oxygen radicals. Excessive production of oxygen radicals leads to muscle atrophy and weakness. We recently generated a mouse model in which one important peroxisome-related gene is missing in skeletal muscles. This model indicates that the peroxisomes are critically important in regulating skeletal muscle size and function under normal conditions. The contribution of peroxisomes to the regulation of muscle size and function under pathological conditions that lead to atrophy and weakness is unknown. In this proposal, we will assess the effects of three muscle atrophy-inducing conditions (acute starvation, sepsis, and denervation) on peroxisome function and turnover in skeletal muscles of female and male adult mice. We will then assess whether oxygen radicals from peroxisomes and mitochondria lead to muscle dysfunction and atrophy in response to these conditions. Finally, we will evaluate whether Depp1 regulates muscle size and function by improving peroxisome and mitochondrial function and quality in skeletal muscles in response to acute starvation, sepsis, and denervation. Our proposal will provide important information about the importance of the peroxisomes and the Depp1 protein in regulating muscle size and function under pathological conditions that cause muscle atrophy.