Project Summary/Abstract Type 2 diabetes (T2D) is a widespread metabolic disorder that is characterized by insulin resistance and hyperglycemia. Obesity, the excess accumulation of fat mass, is a major T2D risk factor and is strongly associated with insulin resistance in skeletal muscle and liver, resulting in less glucose uptake by both organs. Reduced muscle glucose uptake contributes to chronic hyperglycemia and is further exacerbated by excessive hepatic gluconeogenesis. Because skeletal muscle is the largest tissue depot available for glucose disposal, sarcopenia, the loss of skeletal muscle mass, also contributes to hyperglycemia. Though obesity and sarcopenia are key factors that contribute to the pathogenesis of T2D, current therapies address insulin availability or sensitivity without addressing the underlying imbalance between fat and muscle mass. Disruption of the skeletal muscle mitochondrial pyruvate carrier (MPC) increases insulin sensitivity and accelerates fat loss with complete muscle mass sparing in mice recovering from obesity. Thus, modulating skeletal muscle pyruvate metabolism may be useful for treating altered body composition as a T2D root cause. Our previous work has focused on understanding how muscle-specific MPC disruption increases fat oxidation. However, how skeletal muscle MPC disruption maintains lean mass during fat mass loss is still not understood. Therefore, the overall goal of this proposal is to understand how disrupting skeletal muscle mitochondrial pyruvate uptake spares muscle mass during recovery from obesity. Based on our preliminary data, the central hypothesis of this proposal is that muscle MPC disruption leads to muscle mass sparing during recovery from obesity through: 1) a whole-body mechanism of altered substrate exchange between muscle and liver that spares nitrogen for muscle mass; and 2) a unique, MPC disruption-dependent, muscle-autonomous mechanism of nitrogen retention. Experiments for specific aim 1 will test the hypothesis that muscle MPC disruption increases Cori Cycling, the exchange of lactate and glucose between muscle and liver, which spares nitrogen for skeletal muscle protein and amino acid synthesis during weight loss and recovery from obesity. Experiments for specific aim 2 will test the hypothesis that skeletal muscle MPC disruption increases aspartate and branched-chain amino acid (BCAA) availability that leads to maintenance of myocellular protein content. This research is significant because completion will provide mechanistic information on a way to alter skeletal muscle metabolism that may inform treatment of obesity and sarcopenia contributing to T2D. This research is novel because it addresses new concepts in cellular and systemic nitrogen handling.

Project Narrative The proposed research addresses the major public health issue of obesity during Type 2 Diabetes. It investigates how changing the way skeletal muscle utilizes pyruvate may preserve muscle mass when weight is lost during recovery from obesity. Thus, the proposed research is relevant to the NIH’s mission of pursuing fundamental knowledge to improve health outcomes.