Molecular Mechanisms of Exercise Benefits to Insulin Resistant People

Identification of the molecular regulatory points of exercise benefits is of high national priority because of the opportunity to develop targeted novel therapeutics benefiting populations suffering from inactivity-related health problems, including T2DM and pre-diabetes, characterized by insulin resistance (IR). IR is most prevalent in the older population associated with sarcopenia. The investigators propose a novel metabolic regulatory role of PGC-1α4 (α4), a hypertrophy gene, enhanced by resistance exercise (RE). Based on substantial preliminary data, the investigators hypothesize that α4, in cooperation with PPARβ (Rβ), promotes muscle glycolysis and insulin sensitivity (IS) as well as increasing muscle mass and performance. Based on their novel preliminary data, they will also investigate whether by deacetylation of glycolytic proteins, RE enhances muscle glycolytic capacity. Rβ also reduces oxidative stress that not only enhances IS but also contributes to other health benefits. New mRNA based data indicates that RE reduces protein degradation which will be investigated in the current proposal. The investigators will determine whether 3 months of RE training enhances insulin sensitivity and muscle performance and mass in IR people through pathways of enhanced glycolysis, deacetylation of glycolytic proteins reducing protein degradation and enhancing synthesis and ameliorating oxidative stress. They will study 48 IR people 50-75 yrs before and after 3 months of either 4-times/week resistance training or sedentary life and compare them with lean IS people. They will collect vastus lateralis muscle biopsy samples before and after an acute exercise bout and following a mixed meal to measure markers of glycolysis, energy metabolites, glycogen synthase, glycogen content, α4, Rβ, insulin signaling proteins and proteome analysis. They will also measure markers of oxidative stress including 8-OXO-dg (measure of DNA damage), oxidative damage to proteins and subsequent muscle protein degradation, which they hypothesize is reduced by increased anti-oxidant effect of Rβ with RE training. They also will use in vivo labeling of specific muscle proteins utilizing stable isotope labeled tracers to determine whether α4 induced muscle hypertrophy occurs not only by reducing degradation but also by enhancing contractile protein synthesis. These studies will render the necessary mechanistic explanation on how RE enhances IS, glycolysis, reduces oxidative stress and promote muscle performance and mass in IR people, thus substantially contributing to health and life span.