Regulation of Skeletal Muscle Anabolic Resistance in Obesity

Skeletal muscle resistance to anabolic stimuli, such as nutrients, insulin, or resistance exercise, is a major problem for the obese, aged, and other conditions manifested by insulin resistance. Accordingly, there are an estimated 26 million adults in the United States who have been diagnosed with diabetes, 90–95% of which have type 2 diabetes. The population of individuals diagnosed and living with type 2 diabetes is projected to double by 2050, given that obesity rates continue to rise in all demographics and that individuals are living longer with type 2 diabetes. A loss of muscle mass and function promotes disability and are independent predictors of mortality, both of which are exacerbated during obesity. Reduced function promotes inactivity, which is a potent inducer of muscle atrophy, metabolic disequilibrium, and reduced insulin sensitivity. These anabolic effects of insulin and nutrients on skeletal muscle can be inhibited by counter regulatory hormones and cytokines, which are often elevated in the obesity. However, there is a limited understanding of the discriminate mechanisms that contribute to anabolic resistance and loss of skeletal muscle mass as obesity develops and progresses. Therefore, the objective of this proposal is to understand the role of the protein regulated in development and DNA damage responses 1 (REDD1) on the regulation of anabolic stimulation of skeletal muscle adaptation to long-term nutrient interventions. The central hypothesis to be tested is that limiting an increase in REDD1 expression during obesity will augment skeletal muscle anabolic action and phenotype through the regulation of skeletal muscle growth signaling and autophagy. Using a novel conditional REDD1 knockout mouse model in combination with nutrient excess or restriction, the role of REDD1 on whole and tissue phenotype and metabolism during obesity will be determined in Aim 1. In Aim 2 regulators of REDD1’s role on anabolic resistance. The last aim will examine the impact of REDD1 and autophagy on anabolic resistance during obesity. Findings from this research will reveal an innovative nutrient-regulated mechanism of anabolic action and metabolism in skeletal muscle during obesity that could be manipulated pharmacologically, resulting in new and innovative approaches to prevent and treat anabolic resistance.