Evidence from DNA microarray analysis of skeletal muscle that testosterone reverses multiple glucocorticoid‐induced defects in IGF‐1 signaling networks.

Glucocorticoids are an important cause of muscle atrophy. Testosterone replacement therapy attenuates muscle loss due to glucocorticoid administration although virtually nothing is known about its mechanisms. Purpose: To identifying genes that were regulated in opposite directions by glucocorticoids and testosterone. Methods: Male Wistar rats were administered 7 days of treatment with dexamethasone (0.7 mg/kg), dexamethasone plus testosterone (0.7 mg/kg/and 28 mg/kg, respectively), or vehicle. Gene expression was profiled in gastrocnemius muscle using DNA microarrays. Results: A total of 2890 genes were increased in expression by at least 2‐fold after dexamethasone administration, whereas 144 genes were decreased in expression by at least 50% by this treatment. Testosterone blocked upregulation by dexamethasone of 503 genes, approximately 90 of which had known functions, including regulatory molecules such as IGFBP3 and 6, culin4A, GADD45alpha and gamma, and FOXO1A and its downstream targets, MuRF1, MAFbx. Testosterone prevented downregulation by dexamethasone of 71 genes, 20 of which had known functions, including two regulatory molecules, IGFBP5 and IRS‐1. Conclusions: Thus, testosterone acts to prevent multiple changes in expression of multiple factors in IGF‐1 signaling induced in skeletal muscle by dexamethasone. Funded by the Department of Veterans Affairs RR&D Service.