Stem Cell Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
Am J Pathol. 2011 Aug;179(2):915-30. doi: 10.1016/j.ajpath.2011.04.008. Epub 2011 May 31.
Recovery from skeletal muscle injury is often incomplete because of the formation of fibrosis and inadequate myofiber regeneration; therefore, injured muscle could benefit significantly from therapies that both stimulate muscle regeneration and inhibit fibrosis. To this end, we focused on blocking myostatin, a member of the transforming growth factor-β superfamily and a negative regulator of muscle regeneration, with the myostatin antagonist follistatin. In vivo, follistatin-overexpressing transgenic mice underwent significantly greater myofiber regeneration and had less fibrosis formation compared with wild-type mice after skeletal muscle injury. Follistatin's mode of action is likely due to its ability to block myostatin and enhance neovacularization. Furthermore, muscle progenitor cells isolated from follistatin-overexpressing mice were significantly superior to muscle progenitors isolated from wild-type mice at regenerating dystrophin-positive myofibers when transplanted into the skeletal muscle of dystrophic mdx/severe combined immunodeficiency mice. In vitro, follistatin stimulated myoblasts to express MyoD, Myf5, and myogenin, which are myogenic transcription factors that promote myogenic differentiation. Moreover, follistatin's ability to enhance muscle differentiation is at least partially due to its ability to block myostatin, activin A, and transforming growth factor-β1, all of which are negative regulators of muscle cell differentiation. The findings of this study suggest that follistatin is a promising agent for improving skeletal muscle healing after injury and muscle diseases, such as the muscular dystrophies.
骨骼肌损伤的恢复常常不完全，这是因为纤维化的形成和肌纤维再生不足；因此，受伤的肌肉可以从既能刺激肌肉再生又能抑制纤维化的治疗中显著获益。为此，我们专注于阻断肌肉生长抑制素（myostatin），一种转化生长因子-β超家族的成员，也是肌肉再生的负调控因子，使用肌肉生长抑制素拮抗剂卵泡抑素（follistatin）。在体内，与野生型小鼠相比，卵泡抑素过表达的转基因小鼠在骨骼肌损伤后经历了显著更大的肌纤维再生和更少的纤维化形成。卵泡抑素的作用模式可能归因于其阻断肌肉生长抑制素和增强新血管形成的能力。此外，从卵泡抑素过表达的小鼠中分离的肌肉祖细胞在移植到肌营养不良症 mdx/严重联合免疫缺陷小鼠的骨骼肌中再生肌营养不良蛋白阳性肌纤维时，明显优于从野生型小鼠中分离的肌肉祖细胞。在体外，卵泡抑素刺激成肌细胞表达 MyoD、Myf5 和 myogenin，这些都是促进成肌分化的肌源性转录因子。此外，卵泡抑素增强肌肉分化的能力至少部分归因于其阻断肌肉生长抑制素、激活素 A 和转化生长因子-β1 的能力，所有这些都是肌肉细胞分化的负调控因子。这项研究的结果表明，卵泡抑素是一种有前途的药物，可用于改善损伤后和肌肉疾病（如肌肉营养不良症）的骨骼肌愈合。
