Role of Ca2+/calmodulin kinases in skeletal muscle glucose transport and growth.

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DESCRIPTION (provided by applicant): Skeletal muscle metabolic dysfunction and atrophy are prominent features of a number of devastating diseases, including diabetes and cancer, and can also occur in healthy individuals in response to aging and inactivity. Intracellular Ca2+ is a key regulator of many processes in skeletal muscle, including metabolism and growth, yet surprisingly the signaling mechanisms by which Ca2+ regulates these critical functions remain largely unknown. Recent work from my postdoctoral studies has identified the Ca2+-sensitive serine/ threonine kinase, Ca2+/calmodulin-dependent protein kinase kinase alpha (CaMKKalpha), as a novel regulator of contraction-induced glucose transport in skeletal muscle. Importantly, we found that CaMKKalpha regulates glucose transport independent of the AMP-activated protein kinase, a signaling protein already implicated in this process. Thus, the downstream mechanism by which CaMKKalpha mediates glucose transport is not known, and the identification of this substrate is the focus of Specific Aim 1. In addition, exciting preliminary data from my studies suggest a positive role for CaMKKalpha in the regulation of skeletal muscle mass via the mammalian target of rapamycin (mTOR) signaling cascade, a pathway that regulates protein synthesis. Thus, the goal of Specific Aims 2 and 3, the focus of my independent research studies, is to determine the role of CaMKKalpha in the regulation of skeletal muscle growth and protein synthesis. The significance of this work is that elucidation of the signaling proteins involved in these key processes should lead to the development of new treatments for muscle metabolic and wasting disorders associated with many diseases, including diabetes and cancer. PUBLIC DESCRIPTION: Impaired metabolic function and loss of muscle mass are prominent features of a large number of devastating diseases, including diabetes and cancer, and can also occur in healthy individuals in response to aging and inactivity. Our goal is to determine the role that the intracellular protein, Ca2+/calmodulin-dependent protein kinase kinase alpha, plays in the regulation of skeletal muscle glucose metabolism and growth. Understanding the pathways involved in these key processes should lead to the development of better pharmaceutical treatments for muscle metabolic and wasting disorders associated with numerous diseases, including diabetes and cancer.