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.

Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

“…Moreover, muscle mfn2 protein levels were repressed in several catabolic conditions [62][63][64][65]. Lokireddy et al showed that Dex increased mfn2 degradation in myotubes [66], and Liu et al found that Dex decreased mfn2 levels in the TA muscles of mice [12], while Troncoso et al reported that Dex had no influence on mfn2 expression in myotubes [67]. Our results suggested that Dex significantly decreased mfn2 expression levels in skeletal muscle both in vivo and in vitro.…”

Mitochondrial fission – a drug target for cytoprotection or cytodestruction?

“…This suggests a regulatory role for mitochondrial fission in mitochondrial quality control in skeletal muscles via activation of autophagy (Troncoso et al. ). Mitochondrial dynamics also play a significant role in the myogenic differentiation of myoblasts.…”

Ferulic acid attenuates brain microvascular endothelial cells damage caused by oxygen-glucose deprivation via punctate-mitochondria-dependent mitophagy

“…Mitophagy is controlled by various factors and the signalling pathways involved are extremely complicated. It was research has shown that under the stimulation of free radicals, the mitochondrial fission protein Drp1 (dynamin-related protein-1) mediated a tubular mitochondrial split into punctate mitochondria (Troncoso et al, 2014). This dynamic process is necessary for the occurrence of mitochondrial autophagy and plays a vital role in neurodegenerative disease (Saez-Atienzar et al, 2014).…”