Center for Genetic Muscle Disorders, Hugo W. Moser Research Institute at Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205, USA.
J Cell Sci. 2012 Sep 1;125(Pt 17):3957-65. doi: 10.1242/jcs.090365. Epub 2012 Jun 8.
Skeletal muscle fibrosis is a defining feature of the muscular dystrophies in which contractile myofibers are replaced by fibroblasts, adipocytes and extracellular matrix. This maladaptive response of muscle to repetitive injury is progressive, self-perpetuating and thus far, has been considered irreversible. We have previously shown that myostatin, a known endogenous modulator of muscle growth, stimulates normal muscle fibroblasts to proliferate. Here, we demonstrate that myostatin also regulates the proliferation of dystrophic muscle fibroblasts, and increases resistance of fibroblasts to apoptosis through Smad and MAPK signaling. Inhibition of myostatin signaling pathways with a soluble activin IIB receptor (ActRIIB.Fc) reduces resistance of muscle fibroblasts to apoptosis in vitro. Systemic administration of ActRIIB.Fc in senescent mdx mice, a model of muscular dystrophy, significantly increases the number of muscle fibroblasts undergoing apoptosis. This leads to the reversal of pre-existing muscle fibrosis as determined by histological, biochemical and radiographical criteria. These results demonstrate that skeletal muscle fibrosis can be pharmacologically reversed through induction of fibroblast apoptosis.
骨骼肌纤维化是肌肉营养不良症的一个显著特征，在这种疾病中，收缩肌纤维被成纤维细胞、脂肪细胞和细胞外基质所取代。肌肉对反复损伤的这种适应性反应是进行性的、自我延续的，迄今为止，这种反应被认为是不可逆转的。我们之前已经表明，肌肉生长的已知内源性调节剂——肌肉生长抑制素，可刺激正常肌肉成纤维细胞增殖。在这里，我们证明肌肉生长抑制素还调节营养不良性肌肉成纤维细胞的增殖，并通过 Smad 和 MAPK 信号通路增加成纤维细胞对细胞凋亡的抵抗力。用可溶性激活素 IIB 受体 (ActRIIB.Fc) 抑制肌肉生长抑制素信号通路，可减少体外肌肉成纤维细胞对细胞凋亡的抵抗力。在衰老的 mdx 小鼠（肌肉营养不良症的模型）中全身给予 ActRIIB.Fc，可显著增加正在凋亡的肌肉成纤维细胞数量。这导致通过组织学、生化和影像学标准确定的先前存在的肌肉纤维化逆转。这些结果表明，通过诱导成纤维细胞凋亡可以在药理学上逆转骨骼肌纤维化。
