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 as a new therapeutic target in Duchenne muscular dystrophy / C. De Palma, F. Morisi, S. Cheli, S. Pambianco, V. Cappello, M. Vezzoli, P. Rovere-Querini, M. Moggio, M. Ripolone, M. Francolini, M. Sandri, E. Clementi. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 3:11(2012), pp. e418.e418.1-e418.e418.10. [10.1038/cddis.2012.159]

Autophagy as a new therapeutic target in Duchenne muscular dystrophy

C. De Palma
Primo
;
S. Cheli;S. Pambianco;M. Ripolone;M. Francolini;E. Clementi
Ultimo
2012

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; Duchenne muscular dystrophy; Therapy
Settore BIO/14 - Farmacologia
2012
Article (author)
File in questo prodotto:
File Dimensione Formato  
cddis2012159a.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 3.18 MB
Formato Adobe PDF
3.18 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/219599
Citazioni
  • ???jsp.display-item.citation.pmc??? 135
  • Scopus 203
  • ???jsp.display-item.citation.isi??? 195
social impact