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.