Resistance exercise for protection against glucocorticoids in aged skeletal muscle

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Project Summary/Abstract Glucocorticoid myopathy is the most common noninflammatory myopathy affecting ~60% of those with elevated glucocorticoids. Glucocorticoid myopathy is diagnosed by muscle atrophy and weakness; however, the myopathy includes other symptoms such as insulin resistance. The elderly are particularly vulnerable to the myopathy as aged muscle is more sensitive to glucocorticoids, endogenous glucocorticoid levels are increased more than 50% in the elderly, and therapeutic glucocorticoids that treat conditions like arthritis and cancer are most prevalent in the elderly. While it is known that glucocorticoid myopathy is most prevalent in the elderly, there are a lack of treatments to prevent the myopathy in this highly vulnerable population. Our recent publication suggests resistance exercise could be an immediate way to protect aged muscle from glucocorticoid myopathy. Specifically, we show that a bout of resistance exercise in young muscle reduces nuclear translocation of the glucocorticoid receptor, a critical step in the process by which glucocorticoids initiate myopathy. The ability of resistance exercise to blunt nuclear translocation by is particularly important for the elderly because activation of the receptor induces a more severe myopathy in aged muscle. Also important for the elderly population, we show that receptor translocation is reduced in the post exercise recovery period, suggesting that a single bout of resistance exercise could have a lasting protective effect against glucocorticoids. A muscle targeted approach like resistance exercise will also allow elderly patients taking prescription glucocorticoids to keep getting therapeutic benefits of the hormone in non-muscle tissue (e.g. cancerous tumor). In extension of that work, our preliminary data show that a bout of resistance exercise can prevent the glucocorticoid-induced change in the expression of some target genes, while others appear resistant to the exercise stimulus. Because the elderly are so vulnerable to glucocorticoid myopathy, and because glucocorticoids influence expression of up to 20% of the genome, it is important to understand the capacity of resistance exercise to blunt the signals that initiate glucocorticoid myopathy in aged muscle so that clinicians can clinicians more effectively treat these elderly patients. Thus, the objective of this proposal is to define the therapeutic potential of resistance exercise to mitigate processes that initiate glucocorticoid myopathy in aged skeletal muscle. SPECIFIC AIM 1 will Define the steps within the glucocorticoid receptor activation process where resistance exercise imparts disruption in young and aged muscle. SPECIFIC AIM 2 will classify and characterize the glucocorticoid target genes in young and aged muscle based upon how a bout of resistance exercise affects hormone-regulated gene expression. This pilot study will define the extent to which resistance exercise can blunt the signals that initiate glucocorticoid myopathy in aged skeletal muscle. These outcomes are significant because they will provide key information for clinicians to effectively use resistance exercise as part of a comprehensive strategy to prevent glucocorticoid myopathy in the elderly.