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Blocking the myostatin signal with a dominant negative receptor improves the success of human myoblast transplantation in dystrophic mice.

ABSTRACT: Duchenne muscular dystrophy (DMD) is a recessive disease caused by a dystrophin gene mutation. Myoblast transplantation permits to introduce the dystrophin gene in dystrophic muscle fibers. However, the success of this approach is reduced by the short duration of the regeneration following the transplantation, which reduces the number of hybrid fibers. Myostatin (MSTN) is a negative regulator of skeletal muscle development and responsible for limiting regeneration. It binds with high affinity to the activin type IIB receptor (ActRIIB). Our aim was to verify whether the success of the myoblast transplantation is enhanced by blocking the MSTN signal with expression of a dominant negative mutant of ActRIIB (dnActRIIB). In vitro, blocking MSTN activity with a lentivirus carrying dnActRIIB increased proliferation and fusion of human myoblasts because MSTN regulates the expression of several myogenic regulatory factors. In vivo, myoblasts infected with the dnActRIIB lentivirus were transplanted in immunodeficient dystrophic mice. Dystrophin immunostaining of tibialis anterior (TA) cross-sections of these mice 1 month post-transplantation revealed more human dystrophin-positive myofibers following the transplantation of dnActRIIB myoblasts than of control myoblasts. Thus, blocking the MSTN signal with dnActRIIB improved the success of myoblast transplantation by increasing the myoblast proliferation and fusion and changed the expression of myogenic regulatory factors.

SUBMITTER: Fakhfakh R

PROVIDER: S-EPMC3017433 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Blocking the myostatin signal with a dominant negative receptor improves the success of human myoblast transplantation in dystrophic mice.

Fakhfakh Raouia R Michaud Annick A Tremblay Jacques P JP

Molecular therapy : the journal of the American Society of Gene Therapy 20100810 1

Duchenne muscular dystrophy (DMD) is a recessive disease caused by a dystrophin gene mutation. Myoblast transplantation permits to introduce the dystrophin gene in dystrophic muscle fibers. However, the success of this approach is reduced by the short duration of the regeneration following the transplantation, which reduces the number of hybrid fibers. Myostatin (MSTN) is a negative regulator of skeletal muscle development and responsible for limiting regeneration. It binds with high affinity to ...[more]

PMID: 20700111

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Project description:UnlabelledDuchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is the most common muscular dystrophy. Characterized by rounds of muscle degeneration and regeneration, DMD features progressive muscle wasting and is fatal. One approach for treatment is transplantation of muscle progenitor cells to repair and restore dystrophin expression to damaged muscle. However, the success of this approach has been limited by difficulties in isolating large numbers of myogenic progenitors with strong regenerative potential, poor engraftment, poor survival of donor cells, and limited migration in the diseased muscle. We demonstrate that induction of the transcription factor CCAAT/enhancer-binding protein ? (C/EBP?) using the cyclic adenosine monophosphate phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) results in enhanced myoblast expansion in culture and increased satellite cell marker expression. When equal numbers of IBMX-treated cells were transplanted into dystrophic muscle, they contributed to muscle repair more efficiently than did vehicle-treated cells and engrafted into the satellite cell niche in higher numbers, demonstrating improved cell migration from the site of injury and enhanced survival after transplantation. Thus, pharmacologic stimulation of C/EBP? expression reprograms myoblasts to a more stem cell-like state, promotes expansion in culture, and improves engraftment such that better transplantation outcomes are achieved.SignificanceDuchenne muscular dystrophy is a genetic disorder for which no cure exists. One therapeutic approach is transplantation of myogenic progenitors to restore dystrophin to damaged muscle, but this approach is limited by poor engraftment of cultured myoblasts. Transient upregulation of CCAAT/enhancer-binding protein ? in primary myoblasts using the phosphodiesterase isobutylmethylxanthine (IBMX) increases satellite cell marker expression in cultured myoblasts, improves their migration, and increases their survival after transplantation. When transplanted into C57BL/10ScSn-mdx/J mice , IBMX-treated myoblasts restored dystrophin expression and were able to occupy the satellite cell niche more efficiently than controls. A myoblast culture approach that reprograms myoblasts to a more primitive state, resulting in improved transplantation outcomes and reinvigorating research into myoblast transplantation as a viable therapeutic approach, is described.

Project description:BackgroundGrowth differentiation factor 11 (GDF11) is a member of the transforming growth factor β superfamily. The GDF11 propeptide, which is derived from the GDF11 precursor protein, blocks the activity of GDF11 and its homolog, myostatin, which are both potent inhibitors of muscle growth. Thus, treatment with GDF11 propeptide may be a potential therapeutic strategy for diseases associated with muscle atrophy like sarcopenia and the muscular dystrophies. Here, we evaluate the impact of GDF11 propeptide-Fc (GDF11PRO-Fc) gene delivery on skeletal muscle in normal and dystrophic adult mice.MethodsA pull-down assay was used to obtain physical confirmation of a protein-protein interaction between GDF11PRO-Fc and GDF11 or myostatin. Next, differentiated C2C12 myotubes were treated with AAV6-GDF11PRO-Fc and challenged with GDF11 or myostatin to determine if GDF11PRO-Fc could block GDF11/myostatin-induced myotube atrophy. Localized expression of GDF11PRO-Fc was evaluated via a unilateral intramuscular injection of AAV9-GDF11PRO-Fc into the hindlimb of C57BL/6J mice. In mdx mice, intravenous injection of AAV9-GDF11PRO-Fc was used to achieve systemic expression. The impact of GDF11PRO-Fc on muscle mass, function, and pathological features were assessed.ResultsGDF11PRO-Fc was observed to bind both GDF11 and myostatin. In C2C12 myotubes, expression of GDF11PRO-Fc was able to mitigate GDF11/myostatin-induced atrophy. Following intramuscular injection in C57BL/6J mice, increased grip strength and localized muscle hypertrophy were observed in the injected hindlimb after 10 weeks. In mdx mice, systemic expression of GDF11PRO-Fc resulted in skeletal muscle hypertrophy without a significant change in cardiac mass after 12 weeks. In addition, grip strength and rotarod latency time were improved. Intramuscular fibrosis was also reduced in treated mdx mice; however, there was no change seen in central nucleation, membrane permeability to serum IgG or serum creatine kinase levels.ConclusionsGDF11PRO-Fc induces skeletal muscle hypertrophy and improvements in muscle strength via inhibition of GDF11/myostatin signaling. However, GDF11PRO-Fc does not significantly improve the dystrophic pathology in mdx mice.

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Blocking the myostatin signal with a dominant negative receptor improves the success of human myoblast transplantation in dystrophic mice.

Publications

Blocking the myostatin signal with a dominant negative receptor improves the success of human myoblast transplantation in dystrophic mice.

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