Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition
Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition
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DOI：
10.1172/jci28520
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发表时间：
2006-11-01
影响因子：
15.9
通讯作者：
Sunada, Yoshihide
中科院分区：
文献类型：
--
作者：
Ohsawa, Yutaka;Hagiwara, Hiroki;Sunada, Yoshihide
Caveolin-3 是 Caveolins 的肌肉特异性亚型，在信号转导中发挥着重要作用。 Caveolin-3 基因的显性阴性突变会导致常染色体显性肢带型肌营养不良症 1C (LGMD1C)，并伴有 Caveolin-3 缺失。然而，导致caveolin-3缺陷型肌肉肌肉萎缩的精确分子机制的鉴定仍然难以捉摸。肌肉生长抑制素是肌肉特异性 TGF-β 超家族的成员，对骨骼肌体积有负调节作用。在这里，我们报道了 Caveolin-3 通过抑制其 I 型受体的激活来抑制肌肉生长抑制素信号传导；随后细胞内效应子 Mad 同源物 2 (Smad2) 发生低磷酸化，并降低下游转录活性。 P104L 突变型 Caveolin-3 转基因小鼠中的 Caveolin-3 缺失导致肌肉萎缩，磷酸化 Smad2 (p-Smad2) 以及肌肉生长抑制素靶基因 p21（也称为 Cdkn1a）增加。通过基因杂交或腹膜内施用另一种抑制剂可溶性 II 型肌生长抑制素受体，引入肌生长抑制素前结构域（一种肌生长抑制素抑制剂），可改善突变型 Caveolin-3 转基因小鼠的肌肉萎缩，同时抑制 p-Smad2 和 p21 水平。这些发现表明，caveolin-3 通常会抑制肌生长抑制素介导的信号，从而防止肌肉萎缩，并且肌生长抑制素信号的过度激活参与 LGMD1C 小鼠模型中肌萎缩的发病机制。肌肉生长抑制素抑制可能是 LGMD1C 患者的一种有前景的治疗方法。
Caveolin-3, the muscle-specific isoform of caveolins, plays important roles in signal transduction. Dominant-negative mutations of the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C) with loss of caveolin-3. However, identification of the precise molecular mechanism leading to muscular atrophy in caveolin-3-deficient muscle has remained elusive. Myostatin, a member of the muscle-specific TGF-beta superfamily, negatively regulates skeletal muscle volume. Here we report that caveolin-3 inhibited myostatin signaling by suppressing activation of its type I receptor; this was followed by hypophos-phorylation of an intracellular effector, Mad homolog 2 (Smad2), and decreased downstream transcriptional activity. Loss of caveolin-3 in P104L mutant caveolin-3 transgenic mice caused muscular atrophy with increase in phosphorylated Smad2 (p-Smad2) as well as p21 (also known as Cdkn1a), a myostatin target gene. Introduction of the myostatin prodomain, an inhibitor of myostatin, by genetic crossing or intraperitoneal administration of the soluble type II myostatin receptor, another inhibitor, ameliorated muscular atrophy of the mutant caveolin-3 transgenic mice with suppression of p-Smad2 and p21 levels. These findings suggest that caveolin-3 normally suppresses the myostatin-mediated signal, thereby preventing muscular atrophy, and that hyper-activation of myostatin signaling participates in the pathogenesis of muscular atrophy in a mouse model of LGMD1C. Myostatin inhibition may be a promising therapy for LGMD1C patients.