Glucocorticoid control of gene expression during skeletal muscle atrophy

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Skeletal muscle wasting, or atrophy, is a major human health issue. Immobilization, nerve damage, cachexia, sepsis, and aging all induce significant and possibly even life-threatening losses in skeletal muscle mass to the point of impairing adequate ambulatory or respiratory function. Adrenal glucocorticoid hormones are also potent inducers of skeletal muscle atrophy. Physiological levels of glucocorticoids support muscle atrophy in sepsis, renal failure, and other catabolic conditions. In addition, synthetic glucocorticoids are commonly prescribed as potent anti-inflammatory drugs but prolonged use leads to debilitating hyperglycemia, insulin resistance, and bone, cartilage, and muscle loss. New "selective" glucocorticoid receptor ligands have been described that repress inflammatory gene expression but are less potent at up- regulation of other classes of glucocorticoid responsive genes, thus showing good pharmaceutical potential. However, none have been evaluated for effects on skeletal muscle. Furthermore, no drugs are currently available to directly alleviate or prevent muscle atrophy under any circumstances, including glucocorticoid treatment. Inhibition of glucocorticoid receptor action selectively in skeletal muscle would present an opportunity to alleviate atrophy under a variety of conditions. Indeed, activation of either the IGF-1 or beta2 adrenergic receptors strongly inhibits glucocorticoid induced atrophy. The molecular details of this inhibition are poorly understood, as is whether distinct or overlapping signal transduction pathways are used by each receptor to block glucocortcoid receptor activity. Therefore, we propose to 1) Determine the relative contribution of MuRFt and MAFbx genes to glucocorticoid induced skeletal muscle atrophy, 2) Evaluate recently developed selective anti-inflammatory glucocorticoid receptor ligands for effects on muscle atrophy and MuRF1 and MAFbx gene transcription, and 3) Investigate molecular details of glucocorticoid-induced regulation of the MuRF1 gene, with particular focus on the opposing actions of IGF-1 and beta2 adrenergic agonists. Newly developed genetic resources, pharmacological tools, and molecular techniques are available to accomplish these aims. Thus, this proposal represents an opportunity to apply new concepts and cutting-edge technology regarding glucocorticoid receptor function directly to the highly medically relevant problem of skeletal muscle atrophy.