Mechanisms of Resistance Exercise Training for Improved Muscle Insulin Sensitivity

PROJECT SUMMARY/ABSTRACT: The current application is an important step towards accomplishing the applicant’s career goal of becoming an independent translational investigator of exercise benefits to human health. Towards that goal, the applicant’s focus is to understand mechanisms of type 2 diabetes (T2D) and its complications. Muscle insulin resistance is a precursor to the development of T2D. Muscle is the primary tissue for insulin mediated glucose disposal, and loss of muscle mass contributes to insulin resistance. Therefore, maintaining muscle mass is key for regulating insulin sensitivity. Resistance exercise training (RET) enhances muscle mass and strength, and improves insulin sensitivity in people with T2D, but mechanisms of RET are unclear. The overarching goal of this application is to identify mechanisms of RET on enhanced metabolism. Synthesis of new protein machinery for improves metabolism in response to exercise training, but it is unclear which metabolic machinery are synthesized. Additionally, emerging data indicate post-translational modifications (PTMs), especially phosphorylation and acetylation, are key intracellular signaling mechanisms for enhancing insulin sensitivity with exercise, and may explain the improvement in insulin sensitivity with resistance exercise training that occurs before the accretion of new muscle proteins. Our preliminary data show that acetylation of glycolytic and contractile proteins are reduced by RET, which we propose enhances glycolytic protein function for rapid ATP supply, thus enhancing insulin sensitivity. In Aim 1, we will utilize an innovative approach to measure synthesis rates of individual muscle proteins using stable isotope labeling in primary human myotubes to determine which proteins have increased synthesis rates in response to RET. In Aim 2, hyperinsulinemic- euglycemic clamps and muscle biopsies will be performed before and after 2 weeks of RET in sedentary people to determine if glycolytic and contractile protein deacetylation or phosphorylation is associated with insulin sensitivity. Together the results from Aims 1 and 2 will unveil new mechanistic targets for understanding how RET influences metabolism. An understudied yet promising molecular target of RET effects is an isoform of the transcriptional coactivator PGC-1α, PGC-1α4. PGC-1α4 is upregulated by RET in humans, and regulates muscle hypertrophy, glycolysis, and insulin sensitivity, but the role of PGC-1α4 in RET-induced muscle protein synthesis is unknown. Using C2C12 myotubes, Aim 3 will determine individual protein synthesis rates, mRNA expression, and post-translational modifications in response to PGC-1α4 overexpression. The results from these studies will reveal downstream targets of RET on muscle glucose metabolism for future investigation, providing a foundation for the applicant’s long-term career goal of establishing a translational research laboratory investigating exercise- mediated effects on metabolism. The individually tailored training plan, outstanding research environment, and multidisciplinary mentoring team provides the applicant an opportunity to learn new research techniques and successfully complete the proposed research projects to develop as an independent translational investigator.