Metabolic dysregulation within skeletal muscle, including insulin resistance, is a major health problem facing older adults. This is a critical factor for type 2 diabetes mellitus (T2DM), a disease afflicting nearly one in every four older adults. Thus, studies concerning the etiology, prevention and treatment of these metabolic disorders specific to older men and women are crucial. To date, there has been a lack of studies, which have addressed whether alterations in skeletal muscle lipid content and the capacity for fat oxidation induced by intervention predict improvements in insulin resistance. Many studies suggest that elevated muscle triglyceride, or intramyocellular lipid (IMCL) content is associated with insulin resistance. However, recent evidence from our group as well as from others suggests a more complex association between IMCL and insulin resistance, one that likely involves the capacity for fat oxidation. Our studies support the hypothesis that dysregulated fatty acid metabolism and the accumulation of muscle lipid may be a mechanism of insulin resistance in previously sedentary older adults. Further, we will provide a detailed rationale regarding the potential therapeutic mechanisms by which exercise may improve insulin resistance in older adults through improved oxidative fatty acid metabolism. We will employ a randomized controlled exercise intervention trial to test the overall hypothesis that exercise-induced improvement in the capacity for fat oxidation in skeletal muscle is a primary factor which predicts improvements in insulin resistance. We will utilize novel magnetic resonance imaging (MRI), histochemical and biochemical approaches to quantify changes in muscle lipid content and distribution and also the amount of contractile tissue (muscle) itself. These changes in will be measured in conjunction with in vivo and in vitro measures of the capacity for fat oxidation and with in vivo measures of insulin resistance. This project will provide novel information concerning specific mechanisms by which exercise enhances the capacity for oxidative metabolism of fatty acids and improves insulin resistance in older adults who are at high risk for the development of T2DM. Ultimately this should help identify mechanisms and therapeutic targets implicated in skeletal muscle metabolic dysregulation.
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