AAV-mediated delivery of a mutated myostatin propeptide ameliorates calpain 3 but not alpha-sarcoglycan deficiency.
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.
Bartoli
M
M
Généthon, CNRS UMR8115, Evry, France.
Poupiot
J
J
Vulin
A
A
Fougerousse
F
F
Arandel
L
L
Daniele
N
N
Roudaut
C
C
Noulet
F
F
Garcia
L
L
Danos
O
O
Richard
I
I
D000818:Animals; D002154:Calpain / Q000172:deficiency* / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007551:Isotonic Contraction; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009154:Mutation; D055435:Myostatin; D049031:Sarcoglycans / Q000172:deficiency* / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics
C525912:Mstn protein, mouse; D055435:Myostatin; D049031:Sarcoglycans; D016212:Transforming Growth Factor beta; D002154:Calpain