Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia
Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia
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DOI：
10.1016/j.bbrc.2009.12.123
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发表时间：
2010-01-15
影响因子：
3.1
通讯作者：
Zimmers, Teresa A.
中科院分区：
文献类型：
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作者：
Klimek, Margaret E. Benny;Aydogdu, Tufan;Zimmers, Teresa A.
恶病质，尽管营养充足，脂肪和肌肉质量的进行性损失，是与生活质量差和死亡率增加相关的癌症的毁灭性并发症。肌生长抑制素是一种有效的肌肉生长抑制剂。我们使用遗传学和药理学方法测试了肌生长抑制素抑制如何影响癌症恶病质。首先，向肌肉过多的肌生长抑制素缺失小鼠注射刘易斯肺癌或B16 F10黑色素瘤细胞。肌肉生长抑制素基因敲除小鼠对肿瘤诱导的恶病质更敏感，与野生型小鼠相比，绝对质量和肌肉质量损失更多。然而，由于肌生长抑制素基因敲除小鼠缺乏发育表达，我们还试图急性操纵肌生长抑制素。组蛋白去乙酰化酶抑制剂曲古抑菌素A已被证明通过诱导肌生长抑制素抑制剂卵泡抑素来增加正常和营养不良小鼠的肌肉质量。尽管曲古抑菌素A给药在正常小鼠中诱导肌肉生长，但在结肠癌恶病质中未能保护肌肉。最后，我们试图通过施用激活素受体胞外结构域/Fc融合蛋白ACVR 2B-Fc来抑制肌生长抑制素和相关配体。ACVR 2 B-Fc全身给药可有效抑制结肠癌26和刘易斯肺癌恶病质中的肌肉萎缩并保护脂肪储存，而不影响肿瘤生长。肌生长抑制素基因敲除后恶病质增强表明宿主来源的肌生长抑制素不是癌症中肌肉萎缩的唯一介质。更重要的是，用ACVR 2B-Fc保存骨骼肌确立了使用ACVR 2B-Fc或相关分子靶向肌肉生长抑制素家族配体是癌症恶病质中重要且有效的治疗途径。(c)2009 Elsevier Inc. All rights reserved.
Cachexia, progressive loss of fat and muscle mass despite adequate nutrition, is a devastating complication of cancer associated with poor quality of life and increased mortality. Myostatin is a potent tonic muscle growth inhibitor. We tested how myostatin inhibition might influence cancer cachexia using genetic and pharmacological approaches. First, hypermuscular myostatin null mice were injected with Lewis lung carcinoma or B16F10 melanoma cells. Myostatin null mice were more sensitive to tumor-induced cachexia, losing more absolute mass and proportionately more muscle mass than wild-type mice. Because myostatin null mice lack expression from development, however, we also sought to manipulate myostatin acutely. The histone deacetylase inhibitor Trichostatin A has been shown to increase muscle mass in normal and dystrophic mice by inducing the myostatin inhibitor, follistatin. Although Trichostatin A administration induced muscle growth in normal mice, it failed to preserve muscle in colon-26 cancer cachexia. Finally we sought to inhibit myostatin and related ligands by administration of the Activin receptor extracellular domain/Fc fusion protein, ACVR2B-Fc. Systemic administration of ACVR2B-Fc potently inhibited muscle wasting and protected adipose stores in both colon-26 and Lewis lung carcinoma cachexia, without affecting tumor growth. Enhanced cachexia in myostatin knockouts indicates that host-derived myostatin is not the sole mediator of muscle wasting in cancer. More importantly, skeletal muscle preservation with ACVR2B-Fc establishes that targeting myostatin-family ligands using ACVR2B-Fc or related molecules is an important and potent therapeutic avenue in cancer cachexia. (c) 2009 Elsevier Inc. All rights reserved.