Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model

Dis Model Mech. 2015 Jul 1;8(7):679-90. doi: 10.1242/dmm.018127.

Abstract

Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis.

Keywords: Apoptosis; Autophagy; CTG repeat expansion; Dystrophy; Muscle atrophy; Muscleblind.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Apoptosis / genetics
  • Autophagy / genetics
  • Disease Models, Animal
  • Drosophila Proteins / genetics
  • Drosophila melanogaster / genetics
  • Female
  • Genes, Insect
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Muscular Atrophy / etiology
  • Muscular Atrophy / genetics
  • Muscular Atrophy / pathology
  • Myotonic Dystrophy / etiology*
  • Myotonic Dystrophy / genetics
  • Myotonic Dystrophy / pathology
  • Myotonin-Protein Kinase / genetics
  • Nuclear Proteins / genetics
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • Trinucleotide Repeat Expansion
  • Up-Regulation

Substances

  • DIAP1 protein, Drosophila
  • Drosophila Proteins
  • Inhibitor of Apoptosis Proteins
  • Nuclear Proteins
  • mbl protein, Drosophila
  • TOR Serine-Threonine Kinases
  • Myotonin-Protein Kinase