McCroskery Seumas, Thomas Mark, Platt Leanne, Hennebry Alex, Nishimura Takanori, McLeay Lance, Sharma Mridula, Kambadur Ravi
Animal Genomics, AgResearch, Private Bag 3123, East Street, Hamilton, New Zealand.
J Cell Sci. 2005 Aug 1;118(Pt 15):3531-41. doi: 10.1242/jcs.02482.
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.
已知有许多能够影响肌肉再生的刺激性生长因子。最近有研究表明，中和肌肉生长抑制因子，如肌肉生长抑制素（Mstn；也称为生长分化因子8，Gdf8），也会导致已知具有退化周期的mdx小鼠的肌肉再生增加。然而，Mstn调节肌肉再生的确切机制尚未完全确定。为了研究Mstn在成年骨骼肌再生中的作用，用诺维毒素损伤野生型和肌肉生长抑制素基因敲除（Mstn-/-）小鼠。损伤后48小时，与野生型肌肉相比，在Mstn-/-肌肉的再生部位观察到成肌细胞（MyoD1+）和巨噬细胞（Mac-1+）的迁移加速和增殖增强。Mstn-/-肌肉中的炎症细胞数量下降得更快，这表明Mstn-/-小鼠的炎症细胞反应全过程加速。与这一结果一致，添加重组Mstn可降低体外卫星细胞（SCs）的活化以及成肌细胞和巨噬细胞的趋化运动。对再生肌肉（损伤后28天）的检查还显示，与野生型小鼠相比，Mstn-/-小鼠的核心蛋白聚糖mRNA表达增加，纤维化减少，愈合改善。基于这些结果，我们提出Mstn不仅通过控制卫星细胞的活化，还通过调节成肌细胞和巨噬细胞向损伤部位的迁移来负向调节肌肉再生。因此，Mstn拮抗剂有可能作为治疗明显退化和再生障碍的药物。
