Myostatin Induces Degradation of Sarcomeric Proteins through a Smad3 Signaling Mechanism During Skeletal Muscle Wasting (Retracted Article)
Myostatin Induces Degradation of Sarcomeric Proteins through a Smad3 Signaling Mechanism During Skeletal Muscle Wasting (Retracted Article)
复制标题
DOI：
10.1210/me.2011-1124
复制
发表时间：
2011-11-01
影响因子：
--
通讯作者：
Kambadur, Ravi
中科院分区：
文献类型：
--
作者：
Lokireddy, Sudarsanareddy;McFarlane, Craig;Kambadur, Ravi
泛素介导的蛋白水解是骨骼肌萎缩的标志，表现为对负性生长因子（包括肌生长抑制素）的反应。因此，表征骨骼肌萎缩过程中诱导细胞内和肌节蛋白泛素化的信号传导机制是非常重要的。我们最近将肌生长抑制素表征为肌生成的有效负调节剂，并进一步证明循环中肌生长抑制素水平升高导致肌肉特异性E3连接酶Atrogin-1和肌肉环指蛋白1（MuRF 1）的上调。然而，肌肉生长抑制素调节Atrogin-1和MuRF 1表达的确切信号传导机制，以及响应于过量肌肉生长抑制素而降解的靶向蛋白质，仍有待阐明。在这份报告中，我们已经证明，肌肉生长抑制素信号通过Smad 3（母亲对decapentaplegic同系物3）激活叉头盒O 1和Atrogin-1的表达，这进一步促进泛素化和随后的蛋白酶体介导的关键肌节蛋白的降解。Smad 3信号传导对于MuRF 1的肌生长抑制素依赖性过表达是无效的。虽然Atrogin-1表达的下调挽救了约80%的肌生成抑制素诱导的肌节蛋白损失，但当MuRF 1沉默时仅看到约20%的挽救，这表明Atrogin-1是肌生成抑制素表现骨骼肌萎缩的主要E3连接酶。此外，我们强调Atrogin-1不仅与肌球蛋白重链和轻链相关，而且还泛素化这些肌节蛋白。基于现有的数据，我们提出了一个模型，其中肌肉生长抑制素诱导骨骼肌萎缩通过靶向肌节蛋白通过Smad 3介导的Atrogin-1和叉头框O 1的上调。（分子内分泌学25：1936-1949，2011）
Ubiquitination-mediated proteolysis is a hallmark of skeletal muscle wasting manifested in response to negative growth factors, including myostatin. Thus, the characterization of signaling mechanisms that induce the ubiquitination of intracellular and sarcomeric proteins during skeletal muscle wasting is of great importance. We have recently characterized myostatin as a potent negative regulator of myogenesis and further demonstrated that elevated levels of myostatin in circulation results in the up-regulation of the muscle-specific E3 ligases, Atrogin-1 and muscle ring finger protein 1 (MuRF1). However, the exact signaling mechanisms by which myostatin regulates the expression of Atrogin-1 and MuRF1, as well as the proteins targeted for degradation in response to excess myostatin, remain to be elucidated. In this report, we have demonstrated that myostatin signals through Smad3 (mothers against decapentaplegic homolog 3) to activate forkhead box O1 and Atrogin-1 expression, which further promotes the ubiquitination and subsequent proteasome-mediated degradation of critical sarcomeric proteins. Smad3 signaling was dispensable for myostatin-dependent overexpression of MuRF1. Although down-regulation of Atrogin-1 expression rescued approximately 80% of sarcomeric protein loss induced by myostatin, only about 20% rescue was seen when MuRF1 was silenced, implicating that Atrogin-1 is the predominant E3 ligase through which myostatin manifests skeletal muscle wasting. Furthermore, we have highlighted that Atrogin-1 not only associates with myosin heavy and light chain, but it also ubiquitinates these sarcomeric proteins. Based on presented data we propose a model whereby myostatin induces skeletal muscle wasting through targeting sarcomeric proteins via Smad3-mediated up-regulation of Atrogin-1 and forkhead box O1. (Molecular Endocrinology 25: 1936-1949, 2011)