AAV-mediated delivery of a mutated myostatin propeptide ameliorates calpain 3 but not α-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 a-sarcoglycan gene (SGCA). In the highly regenerative Sgca-null mice, survival of the a-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.

Inhibiting myostatin reverses muscle fibrosis through apoptosis

“…Several strategies to postnatally inhibit myostatin in dystrophic muscle have been developed, including neutralizing antibodies, derivatives of myostatin inhibitory propeptide, viral gene delivery of inhibitory follistatin and others (Bartoli et al, 2007;Bogdanovich et al, 2002;Lee, 2004;Nakatani et al, 2008;Qiao et al, 2008;Wagner et al, 2008). In some but not all studies, postnatal myostatin inhibition has resulted in increased muscle mass and muscle strength with less fibrosis in treated animals compared to controls.…”

“…Reduction of myostatin signaling by a variety of genetic and pharmacological mechanisms results in amelioration of disease features in several mouse models of muscular dystrophy (Bartoli et al, 2007;Bogdanovich et al, 2002;Ohsawa et al, 2006;Parsons et al, 2006;Qiao et al, 2008;Wagner et al, 2002). Mdx mice have a nonsense mutation in the gene for dystrophin and are a genetic model of a common and fatal muscular dystrophy, Duchenne muscular dystrophy (DMD), and a phenotypic model of the less severe, allelic Becker Muscular Dystrophy (Hoffman et al, 1987).…”

Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

“…Muscle atrophy caused by mutant caveolin-3 transgenic mice was dramatically recovered [37]. Myostatin propeptide was used for gene therapy using adenoassociated virus (AAV) vector in LGMD2A caused by mutation in the calpain 3 and LGMD2D caused by mutation in the α-sarcoglycan gene (SGCA) [39]. Interestingly, in calpain 3-deficient mice, muscle mass and force were recovered by myostatin inhibition, whereas in the highly regenerative Sgca-null mice, survival was not improved [39].…”

Targeting the Activin Type IIB Receptor to Improve Muscle Mass and Function in the mdx Mouse Model of Duchenne Muscular Dystrophy

“…Release of active MSTN dimers allows binding to the activin type IIB receptor (ActRIIB), leading to subsequent phosphorylation of SMAD proteins and initiation of gene expression (reviewed by Fedoruk and Rupert). 29 Experimental means to inhibit MSTN, including antibodies directed against MSTN, 21,30 propeptide-mediated inhibition of MSTN, 22 and DNA-based inhibition methods, 31,32 have resulted in increased muscle mass in wild-type mice 30 and an improvement in the dystrophic phenotype in the mdx mouse model of DMD. [21][22][23] Additional ligands bind to ActRIIB, including activin A, NODAL, bone morphogenetic protein 2, bone morphogenetic protein-6/7, and growth/differentiation factor 11.…”