Abstract
Numerous stimulatory growth factors that can influence muscle regeneration are known. Recently, it has been demonstrated that neutralization of muscle growth inhibitory factors, such as myostatin (Mstn; also known as growth differentiation factor 8, Gdf8), also leads to increased muscle regeneration in mdx mice that are known to have cycles of degeneration. However, the precise mechanism by which Mstn regulates muscle regeneration has not yet been fully determined. To investigate the role of Mstn in adult skeletal muscle regeneration, wild-type and myostatin-null (Mstn-/-) mice were injured with notexin. Forty-eight hours after injury, accelerated migration and enhanced accretion of myogenic cells (MyoD1+) and macrophages (Mac-1+) was observed at the site of regeneration in Mstn-/- muscle as compared with wild-type muscle. Inflammatory cell numbers decreased more rapidly in the Mstn-/- muscle, indicating that the whole process of inflammatory cell response is accelerated in Mstn-/- mice. Consistent with this result, the addition of recombinant Mstn reduced the activation of satellite cells (SCs) and chemotactic movements of both myoblasts and macrophages ex vivo. Examination of regenerated muscle (28 days after injury) also revealed that Mstn-/- mice showed increased expression of decorin mRNA, reduced fibrosis and improved healing as compared with wild-type mice. On the basis of these results, we propose that Mstn negatively regulates muscle regeneration not only by controlling SC activation but also by regulating the migration of myoblasts and macrophages to the site of injury. Thus, antagonists of Mstn could potentially be useful as pharmacological agents for the treatment of disorders of overt degeneration and regeneration.
Highlights
Skeletal muscle is damaged and repaired repeatedly throughout life
On the basis of these results, we propose that Mstn negatively regulates muscle regeneration by controlling satellite cells (SCs) activation and by regulating the migration of myoblasts and macrophages to the site of injury
Studies by Wehling et al (Wehling et al, 2000) and Carlson et al (Carlson et al, 1999) indicate that Mstn might function as an inhibitor of SC proliferation, suggesting a role for Mstn in postnatal muscle growth and repair
Summary
Skeletal muscle is damaged and repaired repeatedly throughout life. This capacity for muscle regeneration is imparted by satellite cells (SCs). Injured muscle is infiltrated by inflammatory cells; neutrophils increase substantially in number 1-6 hours after an injury and decline rapidly; whereas macrophages constitute the largest cell population at 12 hours post-injury (Tidball, 1995). Recent studies have demonstrated a direct role for macrophages during the early events of skeletal muscle regeneration (Merly et al, 1999). A transplantation model showed that stimulation of macrophage infiltration resulted in earlier activation of SCs, demonstrating that macrophages play a direct role in muscle regeneration (Lescaudron et al, 1997; Lescaudron et al, 1993)
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