AAV-mediated delivery of a mutated myostatin propeptide ameliorates calpain 3 but not alpha-sarcoglycan deficiency.

Abstract

Myostatin is a negative regulator of muscle mass whose inhibition has been proposed as a therapeutic strategy for muscle-wasting conditions. Indeed, blocking myostatin action through different strategies has proved beneficial for the pathophysiology of the dystrophin-deficient mdx mouse. In this report, we tested the inhibition of myostatin by AAV-mediated expression of a mutated propeptide in animal models of two limb-girdle muscular dystrophies: LGMD2A caused by mutations in the calpain 3 (CAPN3) gene and LGMD2D caused by mutations in the alpha-sarcoglycan gene (SGCA). In the highly regenerative Sgca-null mice, survival of the alpha-sarcoglycan-deficient muscle fibers did not improve after transfer of the myostatin propeptide. In calpain 3-deficient mice, a boost in muscle mass and an increase in absolute force were obtained, suggesting that myostatin inhibition could constitute a therapeutic strategy in this predominantly atrophic disorder.

• Authors: M Bartoli, J Poupiot, A Vulin, F Fougerousse, L Arandel, N Daniele, C Roudaut, F Noulet, L Garcia, O Danos, I Richard
• Journal: Gene therapy (Gene Ther) Vol. 14 Issue 9 Pg. 733-40 (May 2007) ISSN: 0969-7128 [Print] England
• PMID: 17330087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Mstn protein, mouse
• Myostatin
• Sarcoglycans
• Transforming Growth Factor beta
• Calpain

Topics

• Animals
• Calpain (deficiency, genetics)
• Dependovirus (genetics)
• Genetic Engineering
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage, genetics)
• Isotonic Contraction
• Male
• Mice
• Mice, Knockout
• Muscle, Skeletal (metabolism, physiopathology)
• Muscular Dystrophies (metabolism, physiopathology, therapy)
• Mutation
• Myostatin
• Sarcoglycans (deficiency, genetics)
• Transduction, Genetic (methods)
• Transforming Growth Factor beta (antagonists & inhibitors, genetics)