Inhibiting Myostatin with Follistatin Improves the Success of Myoblast Transplantation in Dystrophic Mice

Benabdallah, Basma; Bouchentouf, Manaf; Rousseau, Joël; Bigey, Pascal; Michaud, Annick; Chapdelaine, Pierre; Scherman, Daniel; Tremblay, Jacques P.

doi:10.3727/096368908784153913

Cited by 47 publications

(29 citation statements)

References 27 publications

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“…We hypothesize that the double muscling in trout results at least partly from inactivation of myostatin through the binding of follistatin. Follistatin and follistatin-related protein have been demonstrated to be potent antagonists of myostatin (4,6,37), with the dissociation constant of murine follistatin for myostatin and activin reported to be 12.3 and 1.72 nM, respectively (30). Indeed, overexpression of follistatin in transgenic mice resulted in a marked increase in musculature, greater than that observed in myostatin null mice, suggesting that follistatin may bind other growth/differentiation factors in addition to myostatin, including growth differentiation factor-11 (24) and activin (37).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of follistatin in trout stimulates increased muscling

Medeiros¹,

Phelps²,

Fuentes³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Deletion or inhibition of myostatin in mammals has been demonstrated to markedly increase muscle mass by hyperplasia, hypertrophy, or a combination of both. Despite a remarkably high degree of conservation with the mammalian protein, the function of myostatin remains unknown in fish, many species of which continue muscle growth throughout the lifecycle by hyperplasia. Transgenic rainbow trout (Oncorhynchus mykiss) overexpressing follistatin, one of the more efficacious antagonists of myostatin, were produced to investigate the effect of this protein on muscle development and growth. P(1) transgenics overexpressing follistatin in muscle tissue exhibited increased epaxial and hypaxial muscling similar to that observed in double-muscled cattle and myostatin null mice. The hypaxial muscling generated a phenotype reminiscent of well-developed rectus abdominus and intercostal muscles in humans and was dubbed "six pack." Body conformation of the transgenic animals was markedly altered, as measured by condition factor, and total muscle surface area increased. The increased muscling was due almost exclusively to hyperplasia as evidenced by a higher number of fibers per unit area and increases in the percentage of smaller fibers and the number of total fibers. In several individuals, asymmetrical muscling was observed, but no changes in mobility or behavior of follistatin fish were observed. The findings indicate that overexpression of follistatin in trout, a species with indeterminate growth rate, enhances muscle growth. It remains to be determined whether the double muscling in trout is due to inhibition of myostatin, other growth factors, or both.

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Section: Discussionmentioning

confidence: 99%

Overexpression of follistatin in trout stimulates increased muscling

Medeiros¹,

Phelps²,

Fuentes³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Several approaches have been developed to resolve these problems, among them, the blockade of myostatin and homologous proteins in mdx mice or in normal human myoblasts by follistatin up-regulation or by dnActRIIB expression. These approaches increased the extent of muscle repair and improved the success of myoblast transplantation (measured by the number of dystrophin positive fibers present in mdx mouse muscles) (4,5,11). …”

Section: Introductionmentioning

confidence: 99%

Administration of a Soluble Activin Type IIB Receptor Promotes the Transplantation of Human Myoblasts in Dystrophic Mice

2012

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Duchenne muscular dystrophy (DMD) is a recessive disease caused by a dystrophin gene mutation. Myoblast transplantation permits the introduction of the dystrophin gene into dystrophic muscle fibers. However, this strategy has so far produced limited results. Modulation of transforming growth factor β (TGF-β) superfamily signaling promotes skeletal muscle differentiation and growth and myogenic regeneration. We investigated the possibility that the combination of TGF-β superfamily signaling inhibition with myoblast transplantation might be an effective therapeutic approach in dystrophin deficient patients. In vitro, blocking myostatin and other ligands with a soluble form of the extracellular domain of the activin IIB receptor (ActRIIB/Fc) up-regulated the expression of myogenic differentiation factors and increased human myoblast fusion. In vivo, systemic inhibition of activin IIB receptor signalling by delivery of ActRIIB/Fc increased the success of the myoblast transplantation. This effect was further increased by forcing the mice to swim weekly to induce cycles of muscle degeneration and regeneration. Treatment of dystrophic mice with ActRIIB/Fc led to increased body weight, increased skeletal muscle mass and improved myoblast transplantation. Thus ActRIIB/Fc represents an effective therapeutic strategy for muscular dystrophies, and its effects are enhanced when combined with muscle exercise.

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“…Myostatin inactivation by follistatin thus might offer a novel therapeutic strategy for muscular dystrophy by suppressing the progression of muscle degeneration and permitting skeletal muscle mass restoration. Benabdallah et al (2008) reported that myostatin inhibition by follistatin in combination with myoblast transplantation is a promising novel therapeutic approach for treating muscle wasting in diseases such as Duchenne muscular dystrophy. To provide a background for understanding the function of myostatin and follistatin during muscle degeneration and regeneration in an animal model for DMD, we investigated the distribution and expression of these proteins in skeletal muscle of Mdx mice, using B10 Scott Snells mice as a positive control.…”

Section: Introductionmentioning

confidence: 99%

Expression of Myostatin and Follistatin inMdxMice, an Animal Model for Muscular Dystrophy

et al. 2009

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Follistatin is a functional antagonist of several members of the TGF-β family of secreted signaling factors, including myostatin, the most powerful inhibitor of muscle growth characterized to date. Myostatin inhibition offers a novel therapeutic strategy for muscular dystrophy by restoring skeletal muscle mass and suppressing the progression of muscle degeneration. To assess the potential benefits of follistatin in treating muscle degenerative diseases, we examined the expression of myostatin and follistatin in Mdx mice, a model for Duchenne muscular dystrophy, and in B10 mice as a control. Our results demonstrated a temporary and coincident expression of follistatin and myostatin in both mouse strains, but this expression was significantly higher in Mdx mice than in B10 mice. The maximum expression of follistatin and myostatin in the presence of restoring necrotic muscle was detected 4 weeks after birth in Mdx mice. Interestingly, during the stage of complete regeneration, the absence of myostatin and follistatin proteins and a marked decrease in the expression of both genes were observed 9 weeks after birth in both mouse strains. These findings suggest that follistatin not only blocks myostatin but also allows other activators to function in muscle development, emphasizing that follistatin could be a very potent molecule in combating muscle loss during dystrophies and muscle ageing, disuse, or denervation.

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Inhibiting Myostatin with Follistatin Improves the Success of Myoblast Transplantation in Dystrophic Mice

Cited by 47 publications

References 27 publications

Overexpression of follistatin in trout stimulates increased muscling

Overexpression of follistatin in trout stimulates increased muscling

Administration of a Soluble Activin Type IIB Receptor Promotes the Transplantation of Human Myoblasts in Dystrophic Mice

Expression of Myostatin and Follistatin inMdxMice, an Animal Model for Muscular Dystrophy

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