Age Related Insulin Resistance, Akt/PKB, and Skeletal Muscle Proteolysis

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DESCRIPTION (provided by applicant): Decreases in muscle size and strength are associated with advancing age and type 2 diabetes. Since insulin resistance and type 2 diabetes are commonly observed in older individuals, a good portion of the age-related loss of muscle mass may be due to a decrease in insulin action. A major action of insulin is to suppress skeletal muscle proteolysis, in part, by activating protein kinase B (PKB). PKB is a critical insulin signaling molecule that controls a plethora of cellular functions including glucose uptake, glycogen synthesis, protein synthesis, protein degradation, and gene transcription. Activation of PKB reduces skeletal muscle proteolysis by phosphorylating forkhead box O (FOXO) transcription factors and thereby repressing the expression of atrogin-1 and MURF1, two ubiquitin ligases thought to mediate skeletal muscle proteolysis. Our preliminary data demonstrates increases in total protein degradation rates and ubiquitin-protein conjugates in skeletal muscles of aged mice compared to younger mice. Therefore, our first goal of this AREA proposal is to demonstrate that an increase in the ubiquitin-proteasome proteolytic pathway is responsible for the increase in total protein degradation observed in aged skeletal muscle. Our preliminary data also demonstrates decreases in PKB activity and FOXO transcription factor phosphorylation in aged muscle compared to young muscle. In this regard, our second goal is to demonstrate that the ability of insulin to activate PKB and promote FOXO transcription factor phosphorylation is reduced in aged skeletal muscle. Because PKB controls several critical cellular functions relating to both growth and metabolism, different isoforms of the kinase may provide signaling specificity. Since PKB-1 null transgenic mice are smaller than wildtype or PKB-2 null mice, we believe that PKB-1 controls skeletal muscle proteolysis to a greater extent than PKB-2. Therefore, our third goal of this AREA application is to demonstrate that PKB-1 exerts a greater control of ubiquitin-proteasome dependent proteolysis than PKB-2 by using isoform specific PKB knockout mice. Accomplishing these goals will establish a novel mechanism connecting insulin resistance to age-related loss of muscle mass as well as identify an isoform specific function of PKB. In accordance with the NIH-AREA initiative the goals of this R15 proposal will be accomplished by making undergraduate students an integral part of all research activities.