Myostatin Gene Inactivation Prevents Skeletal Muscle Wasting in Cancer
Myostatin Gene Inactivation Prevents Skeletal Muscle Wasting in Cancer
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DOI：
10.1158/0008-5472.can-14-0057
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发表时间：
2014-12-15
期刊：
影响因子：
11.2
通讯作者：
Freyssenet, Damien G.
中科院分区：
文献类型：
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作者：
Gallot, Yann S.;Durieux, Anne-Cecile;Freyssenet, Damien G.
恶病质是一种肌肉消耗综合征，其显著导致许多晚期癌症患者的发病率和死亡率。然而，很少有人了解这种情况下，骨骼肌的严重损失是如何发生的。在目前的研究中，我们测试了假设，肌肉蛋白肌生长抑制素参与介导恶病质诱导的肌肉萎缩的发病机制，在荷瘤小鼠。肌生长抑制素基因失活可防止植入刘易斯肺癌（LLC）细胞的小鼠或已建立的结直肠癌和恶病质模型Apc（Min/+）小鼠中诱导的骨骼肌质量严重损失。从机制上讲，肌肉生长抑制素的丢失通过抑制萎缩相关基因MuRF 1和MAFbx/Atrogin-1沿着自噬相关基因的表达来减弱肌纤维蛋白水解途径的激活。值得注意的是，肌肉生长抑制素的损失也阻碍了LLC肿瘤的生长，Apc（Min/+）小鼠肠息肉的数量和大小，从而大大增加了两种模型的存活率。LLC模型中的基因表达分析显示，这种表型与参与肿瘤代谢、激活素信号传导和凋亡的基因的表达减少相关。总之，我们的研究结果揭示了肌肉生长抑制素在癌症恶病质发病机制中的重要作用，并将这种情况与肿瘤生长联系起来，这对进一步理解癌症作为一种全身性疾病具有重要意义。（C）2014年AACR。
Cachexia is a muscle-wasting syndrome that contributes significantly to morbidity and mortality of many patients with advanced cancers. However, little is understood about how the severe loss of skeletal muscle characterizing this condition occurs. In the current study, we tested the hypothesis that the muscle protein myostatin is involved in mediating the pathogenesis of cachexia-induced muscle wasting in tumor-bearing mice. Myostatin gene inactivation prevented the severe loss of skeletal muscle mass induced in mice engrafted with Lewis lung carcinoma (LLC) cells or in Apc(Min/+) mice, an established model of colorectal cancer and cachexia. Mechanistically, myostatin loss attenuated the activation of muscle fiber proteolytic pathways by inhibiting the expression of atrophy-related genes, MuRF1 and MAFbx/Atrogin-1, along with autophagy-related genes. Notably, myostatin loss also impeded the growth of LLC tumors, the number and the size of intestinal polyps in Apc(Min/+) mice, thus strongly increasing survival in both models. Gene expression analysis in the LLC model showed this phenotype to be associated with reduced expression of genes involved in tumor metabolism, activin signaling, and apoptosis. Taken together, our results reveal an essential role for myostatin in the pathogenesis of cancer cachexia and link this condition to tumor growth, with implications for furthering understanding of cancer as a systemic disease. (C)2014 AACR.