Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice
Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice
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DOI：
10.1152/ajpregu.00121.2011
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发表时间：
2011-09-01
影响因子：
2.8
通讯作者：
Lynch, Gordon S.
中科院分区：
文献类型：
--
作者：
Murphy, Kate T.;Chee, Annabel;Lynch, Gordon S.
墨菲 KT、奇 A、格里森 BG、纳伊姆 T、斯威德斯基 K、库普曼 R、林奇 GS。抗体定向的肌生长抑制素抑制可增强荷瘤小鼠的肌肉质量和功能。 Am J Physiol Regul Integr Comp Physiol 301：R716-R726，2011。首次发表于 2011 年 6 月 15 日； doi:10.1152/ajpregu.00121.2011.-癌症恶病质描述了许多癌症患者的进行性骨骼肌萎缩和虚弱，并占癌症相关死亡的 20% 以上。我们测试了这样的假设：抗体定向的肌生长抑制素抑制会减轻荷瘤小鼠肌肉的萎缩和功能丧失。十二周大的 C57BL/6 小鼠皮下注射盐水（对照）或 Lewis 肺癌 (LLC) 肿瘤细胞。一周后，小鼠每周注射一次盐水（对照，n = 12；LLC，n = 9）或抗人肌生长抑制素抗体的小鼠嵌合体（PF-354，10 mg.kg(-1).wk(-1)，LLC+PF-354，n = 11），持续5周。注射 LLC 细胞使胫骨前肌 (TA) 的肌肉质量和最大力量减少 8-10% (P < 0.05)，但 PF-354 治疗可防止肌肉萎缩和无力 (P > 0.05)。 LLC 注射后膈肌条的最大比（标准化）力降低（P < 0.05），但 PF-354 治疗后隔膜肌条的最大比（标准化）力没有改善（P > 0.05）。 PF-354 使荷瘤小鼠 TA 和膈肌氧化酶活性分别增强 118% 和 89%（P < 0.05）。与对照组相比，经盐水处理的 LLC 荷瘤小鼠的 TA 肌肉横截面中，非肌原纤维或卫星细胞来源的细胞凋亡高出 140% (P < 0.05)，但在经 PF-354 处理的荷瘤小鼠中没有差异 (P > 0.05)。在癌症恶病质小鼠模型中，抗体定向的肌生长抑制素抑制可减轻骨骼肌萎缩和肌肉产生力量的能力丧失，部分是通过减少细胞凋亡来实现的。肢体肌肉质量和功能的改善凸显了抗体导向的肌生长抑制素抑制对癌症恶病质的治疗潜力。
Murphy KT, Chee A, Gleeson BG, Naim T, Swiderski K, Koopman R, Lynch GS. Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice. Am J Physiol Regul Integr Comp Physiol 301: R716-R726, 2011. First published June 15, 2011; doi:10.1152/ajpregu.00121.2011.-Cancer cachexia describes the progressive skeletal muscle wasting and weakness in many cancer patients and accounts for >20% of cancer-related deaths. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the atrophy and loss of function in muscles of tumor-bearing mice. Twelve-week-old C57BL/6 mice received a subcutaneous injection of saline (control) or Lewis lung carcinoma (LLC) tumor cells. One week later, mice received either once weekly injections of saline (control, n = 12; LLC, n = 9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg.kg(-1).wk(-1), LLC+PF-354, n = 11) for 5 wk. Injection of LLC cells reduced muscle mass and maximum force of tibialis anterior (TA) muscles by 8-10% (P < 0.05), but the muscle atrophy and weakness were prevented with PF-354 treatment (P > 0.05). Maximum specific (normalized) force of diaphragm muscle strips was reduced with LLC injection (P < 0.05) but was not improved with PF-354 treatment (P > 0.05). PF-354 enhanced activity of oxidative enzymes in TA and diaphragm muscles of tumor-bearing mice by 118% and 89%, respectively (P < 0.05). Compared with controls, apoptosis that was not of myofibrillar or satellite cell origin was 140% higher in TA muscle cross sections from saline-treated LLC tumor-bearing mice (P < 0.05) but was not different in PF-354-treated tumor-bearing mice (P > 0.05). Antibody-directed myostatin inhibition attenuated the skeletal muscle atrophy and loss of muscle force-producing capacity in a murine model of cancer cachexia, in part by reducing apoptosis. The improvements in limb muscle mass and function highlight the therapeutic potential of antibody-directed myostatin inhibition for cancer cachexia.