Calcineurin-NFAT signaling regulates atrogin-1 and MuRF1 via microRNA-23a (miR-23a) during muscle atrophy

Abstract

Muscle atrophy is prevalent in chronic kidney disease (CKD) patients. MicroRNAs play a critical role in biological processes including muscle atrophy. MicroRNA-23a (miR-23a) negatively regulates the expression of two atrophy-related ubiquitin ligases, atrogin-1 and MuRF1; it is reduced in muscle during atrophy. Although miR-23a expression was recently shown to be positively regulated by NFATc3, the underlying mechanism of miR-23a suppression during atrophy remains unknown. We previously reported that the activity of calcineurin (Cn), the calcium-activated phosphatase that regulates NFATc proteins, is decreased when insulin signaling is decreased. Since CKD causes muscle atrophy, and glucocorticoids are required for the response, we investigated how dexamethasone (DEX) affects Cn activity, NFATc3 signaling, and miR-23a expression. C2C12 or L6 myotubes were treated with 100 uM DEX to induce atrophy. Within 1 h, Cn activity was reduced and less NFATc3 was located in the nucleus. Further, miR-23a was also decreased within 30 minutes. After 48 h, expression of the NFATC3 target gene, MCIP1.4, and miR-23a were decreased. Expression of atrogin-1 and MuRF1 were also increased 48 h after DEX. Collectively, these findings indicate the Cn-NFAT signaling pathway may play an important role in the regulation of atrogin-1 and MuRF1 by suppressing miR23a during CKD and glucocorticoid-related muscle atrophy. Support: NIH DK007656; AHA GRNT7660020