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Forkhead box O3 plays a role in skeletal muscle atrophy through expression of E3 ubiquitin ligases Murf-1 and Atrogin-1 in Cushing's syndrome

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AJP Endocrinology and Metabolism

Published online on

Abstract

Cushing's syndrome is caused by overproduction of the adrenocorticotropic hormone (ACTH), which stimulates the adrenal grand to make cortisol. Skeletal muscle wasting occurs in pathophysiological response to Cushing's syndrome. The forkhead box (FOX) protein family has been implicated as a key regulator of muscle loss under conditions such as diabetes and sepsis. However, the mechanistic role of the FOXO family in ACTH-induced muscle atrophy is not understood. We hypothesized that FOXO3a plays a role in muscle atrophy through expression of the E3 ubiquitin ligases, muscle RING finger protein-1 (MuRF-1) and Atrogin-1 in Cushing's syndrome. For establishment of a Cushing's syndrome animal model, Sprague-Dawley rats were implanted with osmotic mini-pumps containing ACTH (40 ng/kg/day). ACTH infusion significantly reduced muscle weight. In ACTH-infused rats, MuRF-1, Atrogin-1, and FOXO3a were upregulated and FOXO3a promoter was targeted by glucocorticoid receptor (GR). Transcriptional activity and expression of FOXO3a was significantly decreased by GR antagonist RU486. Treatment with RU486 reduced MuRF-1 and Atrogin-1 expression in accordance with reduced enrichment of FOXO3a and Pol II on its promoters. Knockdown of FOXO3a prevented Dex-induced MuRF-1 and Atrogin-1 expression. These results indicate that FOXO3a plays a role in muscle atrophy through expression of MuRF-1 and Atrogin-1 in Cushing's syndrome.