Angiotensin II type 1 receptor blockade attenuates TGF-β-induced failure of muscle regeneration in multiple myopathic states
Angiotensin II type 1 receptor blockade attenuates TGF-β-induced failure of muscle regeneration in multiple myopathic states
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DOI：
10.1038/nm1536
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发表时间：
2007-02-01
期刊：
影响因子：
82.9
通讯作者：
Dietz, Harry C.
中科院分区：
文献类型：
--
作者：
Cohn, Ronald D.;van Erp, Christel;Dietz, Harry C.
骨骼肌具有快速修复损伤或疾病的能力（1）。许多患有马凡氏综合征（MFS）的个体，由细胞外肌球蛋白-1缺乏引起，表现出肌病，并且尽管进行体育锻炼，但通常无法增加肌肉质量。有证据表明，MFS的选定表现反映了转化生长因子（TGF）-β的过度信号传导（参考文献。2、3）。TGF-β是一种已知的培养成肌细胞终末分化抑制剂;然而，TGF-β信号传导在体内各种遗传性肌病状态中对疾病发病机制的功能贡献仍然未知（4，5）。在这里，我们表明，增加TGF-β的活性导致失败的肌肉再生中的Rehrin-1缺陷小鼠。通过施用TGF-β中和抗体或血管紧张素II 1型受体阻断剂氯沙坦对TGF-β的全身拮抗作用使体内肌肉结构、修复和功能正常化。此外，我们显示了TGF-β诱导的肌肉再生失败和类似的治疗反应，在肌营养不良蛋白缺陷的杜氏肌营养不良症小鼠模型。
Skeletal muscle has the ability to achieve rapid repair in response to injury or disease(1). Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise. Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-beta (refs. 2,3). TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown(4,5). Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1 deficient mice. Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy.