Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance

Abstract

Glucocorticoids, such as dexamethasone, enhance protein breakdown via ubiquitin–proteasome system. However, the role of autophagy in organelle and protein turnover in the glucocorticoid-dependent atrophy program remains unknown. Here, we show that dexamethasone stimulates an early activation of autophagy in L6 myotubes depending on protein kinase, AMPK, and glucocorticoid receptor activity. Dexamethasone increases expression of several autophagy genes, including ATG5, LC3, BECN1, and SQSTM1 and triggers AMPK-dependent mitochondrial fragmentation associated with increased DNM1L protein levels. This process is required for mitophagy induced by dexamethasone. Inhibition of mitochondrial fragmentation by Mdivi-1 results in disrupted dexamethasone-induced autophagy/mitophagy. Furthermore, Mdivi-1 increases the expression of genes associated with the atrophy program, suggesting that mitophagy may serve as part of the quality control process in dexamethasone-treated L6 myotubes. Collectively, these data suggest a novel role for dexamethasone-induced autophagy/mitophagy in the regulation of the muscle atrophy program.

Keywords: :

• glucocorticoid
• dexamethasone
• autophagy
• mitophagy
• muscle atrophy

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This research was supported by FONDECYT (grant 1120212 to S.L., 3120220 to C.Q., and 11130285 to R.T.), CONICYT (grant Anillo ACT1111 to S.L.; FONDAP 15130011 to S.L. and R.T.). We are thankful for the PhD or MSc fellowships from CONICYT Chile to F.P., A.E.R., D.G., C.V.T., and C.L.C. V.P. thanks to the International Postdoctoral Bicentennial Program from CONICYT, Chile and the American Heart Association. G.K. is financed by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; and the Paris Alliance of Cancer Research Institutes (PACRI). We also thank Fidel Albornoz and Gindra Latorre for their excellent technical assistance.