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.
Highlights
The therapeutic protocols currently in use, based on corticosteroid administration, provide some delay in the progression of the disease, but they are associated with severe side effects.[3,4] Therapies that substitute corticosteroids or at least may act as corticosteroid-sparing drugs are being actively pursued, and biological mechanisms relevant to skeletal muscle homoeostasis are explored, in order to identify new targets
Our results identify autophagy as an important homoeostatic mechanism deranged in dystrophic muscles and indicate that novel therapeutic approaches aimed at reactivating autophagy are a valuable strategy to reduce muscle damage in Duchenne muscular dystrophy (DMD)
We found that phosphorylation of Akt on Ser[473] was significantly increased as it was the phosphorylation of key downstream effectors of mammalian target of rapamycin (mTOR), namely the ribosomal protein S6 and the eukaryotic translation-initiation factor 4E-binding protein 1 (4E-BP1) (Figure 1b)
Summary
The therapeutic protocols currently in use, based on corticosteroid administration, provide some delay in the progression of the disease, but they are associated with severe side effects.[3,4] Therapies that substitute corticosteroids or at least may act as corticosteroid-sparing drugs are being actively pursued, and biological mechanisms relevant to skeletal muscle homoeostasis are explored, in order to identify new targets. Higher levels of activation and phosphorylation of Akt are observed in muscles and primary myoblasts of the mdx mouse model of dystrophy.[13,14] In agreement with this observation, the progressive muscular dystrophic phenotype observed in mdx mice is accompanied by progressively enhanced Akt activation especially at peak necrotic and hypertrophic phases of disease.[14] Such a phenotype has been described in patients affected by DMD.[14] Akt is the most potent inhibitor of autophagy in skeletal muscle, blocking formation of autophagosomes and lysosomal-dependent degradation of their content,[15,16] thereby suggesting a defective autophagic process.
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