Department of Cell Biology & Anatomy, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Biochem Biophys Res Commun. 2010 Jan 15;391(3):1548-54. doi: 10.1016/j.bbrc.2009.12.123. Epub 2009 Dec 28.
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.
恶病质是一种进行性的肌肉和脂肪组织丢失，即使有足够的营养摄入也无法避免，它是与癌症相关的一种破坏性并发症，会导致生活质量下降和死亡率增加。肌肉生长抑制素（myostatin）是一种有效的肌肉生长抑制剂。我们通过基因和药理学方法测试了肌肉生长抑制素抑制作用可能对癌症恶病质的影响。首先，肌肉生长抑制素超表达的纯合子缺失（myostatin null）小鼠被注射 Lewis 肺癌或 B16F10 黑色素瘤细胞。与野生型小鼠相比，肌肉生长抑制素超表达的纯合子缺失（myostatin null）小鼠对肿瘤诱导的恶病质更为敏感，失去了更多的绝对质量和更多的肌肉质量。然而，由于肌肉生长抑制素超表达的纯合子缺失（myostatin null）小鼠从发育开始就缺乏表达，因此我们也试图对肌肉生长抑制素进行急性操作。组蛋白去乙酰化酶抑制剂 Trichostatin A 已被证明通过诱导肌肉生长抑制素抑制剂 follistatin 来增加正常和营养不良小鼠的肌肉质量。虽然 Trichostatin A 给药可诱导正常小鼠的肌肉生长，但在结肠癌 26 恶病质中未能保留肌肉。最后，我们试图通过给予激活素受体细胞外结构域/Fc 融合蛋白 ACVR2B-Fc 来抑制肌肉生长抑制素和相关配体。ACVR2B-Fc 的全身给药可有效抑制肌肉消耗并保护结肠癌 26 和 Lewis 肺癌恶病质中的脂肪储存，而不影响肿瘤生长。肌肉生长抑制素敲除小鼠恶病质的增强表明，宿主来源的肌肉生长抑制素不是癌症肌肉消耗的唯一介质。更重要的是，ACVR2B-Fc 对骨骼肌的保护作用表明，使用 ACVR2B-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的重要和有效治疗途径。
