Selective loss of muscle protein, or sarcopenia, is a significant problem for the elderly, leading to loss of muscle function and reducing the supply of amino acids that are available for mobilization in times of stress, which impacts on clinical outcome. Sarcopenia is undoubtedly multifactorial, including level of physical activity, and nutritional an l hormonal status, but this grant will focus on the contribution of inflammation on sarcopenia. At the tissue level, rates of muscle protein synthesis are reduced in the elderly, as they are in other conditions of injury or inflammation. This grant will investigate the role of inflammation on loss of muscle protein through diminished protein synthesis, and a reduced capacity of muscle protein synthesis to respond to the anabolic effects of hormones such as growth hormone (GH). Rates of muscle protein synthesis will be assessed from the incorporation of L- [2H5]phenylalanine into muscle protein, with distinction between myofibrillar (contractile) and sarcoplasmic (non-contractile) proteins. Rates of muscle protein synthesis will be correlated with markers of inflammation, including the soluble type 2 receptor for tumor necrosis factor (sTNFR-2). It is anticipated that individuals with inflammation will have reduced rates of muscle protein synthesis in the basal state and a diminished capacity to increase muscle protein synthesis in response to GH treatment. Rates of muscle protein synthesis will also be related to abnormalities at the cellular level, including changes in the intracellular signaling cascade for insulin and IGF-I through phosphatidylinositol 3-kinase (PI 3-K). This pathway is important in the regulation of both glucose transport and protein synthesis. Since insulin and insulin-like growth factor I share much of the same signaling cascade, diminished responsiveness of muscle protein synthesis to GH, in those individuals with higher levels of inflammation, should be apparent as a decrease in the intracellular signaling cascade through PI 3-K. Correlating cellular events with serum markers such as sTNFR-2 will provide a means of identifying individuals at risk of sarcopenia. Therapy with an insulin-sensitizing drug, thiazolidinedione, will be used to reduce the effects of TNFalpha on insulin signaling and to improve muscle protein synthesis.
