Format

Send to

Choose Destination
Hum Mol Genet. 2015 Nov 15;24(22):6428-45. doi: 10.1093/hmg/ddv353. Epub 2015 Sep 10.

Ultra-structural time-course study in the C. elegans model for Duchenne muscular dystrophy highlights a crucial role for sarcomere-anchoring structures and sarcolemma integrity in the earliest steps of the muscle degeneration process.

Author information

1
Université Claude Bernard Lyon 1, 43 boulevard du 11 novembre, 69622 Villeurbanne, France, Centre de Génétique et de Physiologie moléculaires et cellulaires, CNRS UMR 5534, 16 rue Dubois, 69622 Villeurbanne, France.
2
Department of Pathology, Emory University, 615 Michael Street, Whitehead 165, Atlanta, GA 30322, USA.
3
Intitut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 964, 1 rue Laurent Fries, BP 10142, 67404 Illkirch CEDEX, France and.
4
Center of Pathology and Neuropathology, East Hospital, Hospices Civils de Lyon, Lyon, France.
5
Université Claude Bernard Lyon 1, 43 boulevard du 11 novembre, 69622 Villeurbanne, France, Centre de Génétique et de Physiologie moléculaires et cellulaires, CNRS UMR 5534, 16 rue Dubois, 69622 Villeurbanne, France, kathrin.gieseler@univ-lyon1.fr.

Abstract

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive muscle degeneration due to mutations in the dystrophin gene. In spite of great advances in the design of curative treatments, most patients currently receive palliative therapies with steroid molecules such as prednisone or deflazacort thought to act through their immunosuppressive properties. These molecules only slightly slow down the progression of the disease and lead to severe side effects. Fundamental research is still needed to reveal the mechanisms involved in the disease that could be exploited as therapeutic targets. By studying a Caenorhabditis elegans model for DMD, we show here that dystrophin-dependent muscle degeneration is likely to be cell autonomous and affects the muscle cells the most involved in locomotion. We demonstrate that muscle degeneration is dependent on exercise and force production. Exhaustive studies by electron microscopy allowed establishing for the first time the chronology of subcellular events occurring during the entire process of muscle degeneration. This chronology highlighted the crucial role for dystrophin in stabilizing sarcomeric anchoring structures and the sarcolemma. Our results suggest that the disruption of sarcomeric anchoring structures and sarcolemma integrity, observed at the onset of the muscle degeneration process, triggers subcellular consequences that lead to muscle cell death. An ultra-structural analysis of muscle biopsies from DMD patients suggested that the chronology of subcellular events established in C. elegans models the pathogenesis in human. Finally, we found that the loss of sarcolemma integrity was greatly reduced after prednisone treatment suggesting a role for this molecule in plasma membrane stabilization.

PMID:
26358775
DOI:
10.1093/hmg/ddv353
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center