Skeletal muscle wasting, or atrophy, is a major human health concern. Immobilization, nerve damage, cachexia, sepsis, and aging induce significant and potentially life-threatening losses in skeletal muscle mass to the point of impairing adequate ambulatory or respiratory function. Adrenal glucocorticoid hormones are potent inducers of skeletal muscle atrophy. Physiological glucocorticoid levels support muscle atrophy in fasting and chronic illness among other catabolic conditions. In addition, synthetic glucocorticoids are used clinically as potent anti-inflammatory drugs with serious side effects such as 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 of these compounds have been evaluated for effects on skeletal muscle. Inhibition of glucocorticoid receptor action selectively in skeletal muscle would present an opportunity to alleviate atrophy under a variety of conditions. In this proposal, we will focus on the role of two recently identified E3 ubiquitin ligases, MuRF1 and MAFbx, in glucocorticoid induced skeletal muscle atrophy, and their transcriptional activation. We propose to 1) determine the relative contribution of MuRF1 and MAFbx genes to glucocorticoid induced skeletal muscle atrophy using mice with selective gene deletions, 2) investigate the role of the glucocorticoid receptor in the induction of muscle atrophy, as well as, MuRF1 and MAFbx expression using mice with a muscle-specific deletion of the glucocorticoid receptor, 3) investigate the role of the glucocorticoid receptor and FOXO proteins in regulating MuRF1 gene expression using chromatin immunoprecipitation assays, and 4) evaluate selective anti-inflammatory glucocorticoid ligands for effects on muscle atrophy and MuRF1 and MAFbx expression. Newly developed genetic resources, pharmacological tools, and molecular techniques are available to accomplish these aims in the investigator's laboratories and through key collaborations. Thus, this proposal represents an opportunity to apply new concepts and cutting-edge technology regarding glucocorticoid receptor function directly to the clinically relevant and unmet problem of skeletal muscle atrophy.
Elevated glucocorticoids contribute to skeletal muscle atrophy under a variety of conditions. However, no drugs are currently available to directly alleviate or prevent muscle atrophy under any circumstance, including glucocorticoid treatment. An understanding of the transcriptional regulation of MuRF1 and MAFbx, and the role of the glucocorticoid receptor in the induction of muscle atrophy should greatly assist in the development of therapeutics to treat muscle atrophy under a variety of conditions.
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