Skeletal muscle metabolic dysfunction and atrophy are prominent features of cachexia, a complex and devastating syndrome characterized by loss of body weight, loss of skeletal muscle and fat mass, and skeletal muscle weakness. Cachexia occurs as a consequence of a broad range of diseases, including uncontrolled hyperglycemia (i.e. diabetes), cancer, chronic lung, heart and kidney diseases, and AIDS;and in these disease states skeletal muscle wasting significantly contributes to disease mortality via a decrease in mobility and an impaired ability to respirate. Skeletal muscle wasting also occurs in healthy individuals as a normal response to aging, or in response to prolonged bouts of inactivity. Given this wide range of affected patients, and the consequences if muscle wasting is not reversed, determination of the cellular and molecular factors underlying the regulation of skeletal muscle mass is a critical undertaking that could lead to the development of pharmaceutical treatments for muscle wasting disorders. In muscle wasting disorders, dysregulation ofthe balance between protein synthesis and protein degradation shifts towards decreased protein synthesis, and this occurs via a decrease in the activation of the mammalian target of rapamycin (mTOR) signaling cascade. Despite the critical role that mTOR plays in regulating muscle mass, the upstream signaling pathways that regulate mTOR are still largely unknown. In this proposal, we present intriguing new data suggesting that the Ca2+-sensitive, serine/threonine kinase, Ca2+/calmodulin-dependent protein kinase kinase alpha (CaMKKalpha) is a novel regulator of skeletal muscle mass and mTOR signaling. Thus, in this application, we propose to investigate the role of CaMKKalpha in the regulation of growth, protein synthesis and mTOR signaling in skeletal muscle.
Impaired metabolic dysfunction and loss of muscle mass are prominent features of many devastating diseases, including diabetes and cancer;and can also occur in healthy people in response to inactivity and aging. Determination of the cellular and molecular factors underlying the regulation of muscle mass could lead to the development of pharmaceutical treatments for muscle wasting disorders.
