An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy
An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy
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DOI：
10.1038/labinvest.2012.78
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发表时间：
2012-08
影响因子：
5
通讯作者：
Y. Ohsawa;T. Okada;S. Nishimatsu;M. Ishizaki;T. Suga;M. Fujino;Tatsufumi Murakami;M. Uchino;
中科院分区：
文献类型：
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作者：
Y. Ohsawa;T. Okada;S. Nishimatsu;M. Ishizaki;T. Suga;M. Fujino;Tatsufumi Murakami;M. Uchino;
小鼠中表达 Pro104Leu 突变型小窝蛋白 3 (CAV3 P104L) 的骨骼肌萎缩，并作为常染色体显性肢带型肌营养不良症 1C 的模型。我们之前发现，caveolin 3 缺陷的肌肉表现出激活的肌内转化生长因子 β (TGF-β) 信号。然而，caveolin 3 缺失导致肌肉萎缩的细胞机制尚不清楚。最近，几种 TGF-β I 型受体 (TβRI) 激酶的小分子抑制剂已被开发为通过抑制细胞内 TGF-β1、-β2 和 -β3 信号传导来治疗癌症的分子靶向药物。在这里，我们证明 TβRI 激酶抑制剂 Ki26894 可在体外恢复由激活素、肌生长抑制素、TGF-β1 以及 CAV3 P104L 引起的受损成肌细胞分化。口服 Ki26894 增加了野生型小鼠体内的肌肉质量和力量，并改善了 CAV3 P104L 小鼠的肌肉萎缩和无力。该抑制剂恢复了卫星细胞（成体骨骼肌常驻干细胞）的数量，同时抑制了效应子 Smad2 磷酸化的增加，以及肌肉中 TGF-β 家族成员的靶基因 p21（也称为 Cdkn1a）的上调。这些数据表明，TGF-β依赖性卫星细胞减少和成肌细胞分化受损均导致caveolin 3缺陷型肌肉萎缩的细胞机制。 TβRI激酶抑制剂可以拮抗肌内抗肌源性TGF-β信号的激活，从而为在各种临床环境中替代使用此类抗癌药物逆转肌肉萎缩提供新的治疗原理。
Skeletal muscle expressing Pro104Leu mutant caveolin 3 (CAV3 P104L) in mouse becomes atrophied and serves as a model of autosomal dominant limb-girdle muscular dystrophy 1C. We previously found that caveolin 3-deficient muscles showed activated intramuscular transforming growth factor beta (TGF-β) signals. However, the cellular mechanism by which loss of caveolin 3 leads to muscle atrophy is unknown. Recently, several small-molecule inhibitors of TGF-β type I receptor (TβRI) kinase have been developed as molecular-targeting drugs for cancer therapy by suppressing intracellular TGF-β1,-β2, and-β3 signaling. Here, we show that a TβRI kinase inhibitor, Ki26894, restores impaired myoblast differentiation in vitro caused by activin, myostatin, and TGF-β1, as well as CAV3 P104L. Oral administration of Ki26894 increased muscle mass and strength in vivo in wild-type mice, and improved muscle atrophy and weakness in the CAV3 P104L mice. The inhibitor restored the number of satellite cells, the resident stem cells of adult skeletal muscle, with suppression of the increased phosphorylation of Smad2, an effector, and the upregulation of p21 (also known as Cdkn1a), a target gene of the TGF-β family members in muscle. These data indicate that both TGF-β-dependent reduction in satellite cells and impairment of myoblast differentiation contribute to the cellular mechanism underlying caveolin 3-deficient muscle atrophy. TβRI kinase inhibitors could antagonize the activation of intramuscular anti-myogenic TGF-β signals, thereby providing a novel therapeutic rationale for the alternative use of this type of anticancer drug in reversing muscle atrophy in various clinical settings.