Muscle myostatin signalling is enhanced in experimental cancer cachexia
Muscle myostatin signalling is enhanced in experimental cancer cachexia
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DOI：
10.1111/j.1365-2362.2008.01970.x
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发表时间：
2008-07-01
影响因子：
5.5
通讯作者：
Fanelli, F. Rossi
中科院分区：
文献类型：
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作者：
Costelli, P.;Muscaritoli, M.;Fanelli, F. Rossi
背景/目的 肌肉生长抑制素属于转化生长因子-β 超家族，对骨骼肌质量具有负调节作用。它的缺失会导致肌肉过度生长，而相反，它的过度表达或全身给药会导致肌肉萎缩。本研究旨在调查癌症恶病质实验模型（携带吉田 AH-130 肝癌的大鼠）中发生的肌肉耗竭是否与肌生长抑制素信号传导相关，以及细胞因子肿瘤坏死因子-α 是否与此相关。 材料和方法 已在小鼠腓肠肌中评估了肌生长抑制素、卵泡抑素（肌生长抑制素内源性抑制剂）和 IIB 型激活素受体的蛋白质水平。通过蛋白质印迹法检测荷瘤大鼠。通过免疫沉淀法评估肿瘤宿主中的循环肌生长抑制素和卵泡抑素，并通过电泳迁移率变动测定测定 SMAD 转录因子的 DNA 结合活性。结果在第 4 天，肿瘤宿主肌肉肌生长抑制素水平与对照相当，但卵泡抑素降低，SMAD DNA 结合活性增强。第 7 天，肿瘤携带者中的肌生长抑制素和卵泡抑素均增加，而 SMAD DNA 结合活性没有变化。为了研究肿瘤坏死因子-α是否导致了这种变化，给大鼠注射了己酮可可碱，这是一种肿瘤坏死因子-α合成的抑制剂，可以部分纠正荷瘤大鼠的肌肉耗竭。该药物在第 4 天的肿瘤宿主中降低了肌生长抑制素的表达和 SMAD DNA 结合活性，并在第 7 天上调了卵泡抑素。结论这些观察结果表明，肌生长抑制素途径应被视为癌症恶病质的潜在治疗靶点。
Background/Aims Myostatin belongs to the transforming growth factor-beta superfamily and negatively regulates skeletal muscle mass. Its deletion induces muscle overgrowth, while, on the contrary, its overexpression or systemic administration cause muscle atrophy. The present study was aimed at investigating whether muscle depletion as occurring in an experimental model of cancer cachexia, the rat bearing the Yoshida AH-130 hepatoma, is associated with modulations of myostatin signalling and whether the cytokine tumour necrosis factor-alpha may be relevant in this regard.Materials and methods Protein levels of myostatin, follistatin (myostatin endogenous inhibitor) and the activin receptor type IIB have been evaluated in the gastrocnemius of tumour-bearing rats by Western blotting. Circulating myostatin and follistatin in tumour hosts were evaluated by immunoprecipitation, while the DNA-binding activity of the SMAD transcription factors was determined by electrophoretic-mobility shift assay.Results In day 4 tumour hosts muscle myostatin levels were comparable to controls, yet follistatin was reduced, and SMAD DNA-binding activity was enhanced. At day 7, both myostatin and follistatin increased in tumour bearers, while SMAD DNA-binding activity was unchanged. To investigate whether tumour necrosis factor-alpha contributed to induce such changes, rats were administered pentoxifylline, an inhibitor of tumour necrosis factor-alpha synthesis that partially corrects muscle depletion in tumour-bearing rats. The drug reduced both myostatin expression and SMAD DNA-binding activity in day 4 tumour hosts and up-regulated follistatin at day 7.Conclusions These observations suggest that myostatin pathway should be regarded as a potential therapeutic target in cancer cachexia.