Autophagy as a new therapeutic target in Duchenne muscular dystrophy

Abstract

A resolutive therapy for Duchene muscular dystrophy, a severe degenerative disease of the skeletal muscle, is still lacking. Because autophagy has been shown to be crucial in clearing dysfunctional organelles and in preventing tissue damage, we investigated its pathogenic role and its suitability as a target for new therapeutic interventions in Duchenne muscular dystrophy (DMD). Here we demonstrate that autophagy is severely impaired in muscles from patients affected by DMD and mdx mice, a model of the disease, with accumulation of damaged organelles. The defect in autophagy was accompanied by persistent activation via phosphorylation of Akt, mammalian target of rapamycin (mTOR) and of the autophagy-inhibiting pathways dependent on them, including the translation-initiation factor 4E-binding protein 1 and the ribosomal protein S6, and downregulation of the autophagy-inducing genes LC3, Atg12, Gabarapl1 and Bnip3. The defective autophagy was rescued in mdx mice by long-term exposure to a low-protein diet. The treatment led to normalisation of Akt and mTOR signalling; it also reduced significantly muscle inflammation, fibrosis and myofibre damage, leading to recovery of muscle function. This study highlights novel pathogenic aspects of DMD and suggests autophagy as a new effective therapeutic target. The treatment we propose can be safely applied and immediately tested for efficacy in humans.

Autophagy regulates satellite cell ability to regenerate normal and dystrophic muscles

“…Despite these data are apparently in contrast with the beneficial effects of autophagy stimulation in dystrophies, our work rather emphasizes the necessity to develop cell-specific strategies to modulate autophagy in the satellite compartment to improve muscle regeneration. Pharmacological approaches that restore the autophagic flux as LPD 24 and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) -an AMP-activated protein kinase (AMPK) agonist - 26 have been proven to be effective in ameliorating muscular functions in mdx mice. Other studies demonstrates that the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6), which regulates autophagy, displays a stage-dependent effect in mdx mice, 25 further supporting the notion that unbalanced autophagy occurs in DMD.…”

“…[21][22][23] Recent investigations have begun to elucidate the role of autophagy in other muscular disorders, including DMD. [24][25][26][27] Moreover, it has been shown that autophagy is implicated in loss of muscle mass in the elderly, referred as sarcopenia, 28,29 as well as in myofiber survival. 30 Multiple lines of evidence indicate that autophagy diminishes with aging, 31 premature aging correlates with autophagy inhibition, 29 while increased autophagy (as by mean of calorie restriction) delays aging and extends longevity.…”

Signaling mechanisms in regenerative myogenesis.

“…Akt signaling is responsible for inhibition of autophagy in mdx mice (111). However, our results demonstrate that TRAF6 regulates autophagy independent of Akt signaling.…”

“…Recently, the role of autophagy in pathogenesis of muscular dystrophy has been investigated using multiple approaches. Autophagy has been found to be impaired in muscle biopsies from patients with DMD and in mdx mice with concomitant accumulation of damaged organelles (111). Notably, reactivation of autophagy by feeding low-protein diet improved muscle strength and various pathological features including fiber necrosis, pathological hypertrophy, and fibrosis in mdx mice (111).…”

“…While basal level of autophagy is required for the maintenance of skeletal muscle mass, excessive autophagosome formation generally leads to muscle-wasting (106)(107)(108)(109)(110). Interestingly, autophagy has been found to be impaired in muscle biopsies from patients with DMD and in skeletal muscle of mdx mice with concomitant accumulation of damaged organelles (111). However, the role of TRAF6 in regulation of autophagy in the "settings" of muscular dystrophy remains unknown.…”