Bonetto A, Penna F, Minero V G, Reffo P, Bonelli G, Baccino F M, Costelli P
Department of Experimental Medicine and Oncology, University of Torino, 10125 Torino, Italy.
Curr Cancer Drug Targets. 2009 Aug;9(5):608-16. doi: 10.2174/156800909789057015. Epub 2009 Aug 1.
Muscle wasting, as occurring in cancer cachexia, is primarily characterized by protein hypercatabolism and increased expression of ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1. Myostatin, a member of the TGFbeta superfamily, negatively regulates skeletal muscle mass and we showed that increased myostatin signaling occurs in experimental cancer cachexia. On the other hand, enhanced expression of follistatin, an antagonist of myostatin, by inhibitors of histone deacetylases, such as valproic acid or trichostatin-A, has been shown to increase myogenesis and myofiber size in mdx mice. For this reason, in the present study we evaluated whether valproic acid or trichostatin-A can restore muscle mass in C26 tumor-bearing mice. Tumor growth induces a marked and progressive loss of body and muscle weight, associated with increased expression of myostatin and ubiquitin ligases. Treatment with valproic acid decreases muscle myostatin levels and enhances both follistatin expression and the inactivating phosphorylation of GSK-3beta, while these parameters are not affected by trichostatin-A. Neither agent, however, counteracts muscle atrophy or ubiquitin ligase hyperexpression. Therefore, modulation of the myostatin/follistatin axis in itself does not appear sufficient to correct muscle atrophy in cancer cachexia.
肌肉萎缩，如癌症恶病质中出现的那样，主要特征为蛋白质分解代谢亢进以及泛素连接酶（如atrogin-1/MAFbx和MuRF-1）的表达增加。肌肉生长抑制素是转化生长因子β超家族的成员，对骨骼肌质量起负调节作用，并且我们发现实验性癌症恶病质中肌肉生长抑制素信号增强。另一方面，组蛋白脱乙酰酶抑制剂（如丙戊酸或曲古抑菌素A）可增强肌肉生长抑制素拮抗剂卵泡抑素的表达，已表明这会增加mdx小鼠的肌生成和肌纤维大小。因此，在本研究中，我们评估了丙戊酸或曲古抑菌素A是否能恢复荷C26肿瘤小鼠的肌肉质量。肿瘤生长会导致体重和肌肉重量显著且逐渐下降，同时伴有肌肉生长抑制素和泛素连接酶表达增加。丙戊酸治疗可降低肌肉中肌肉生长抑制素水平，并增强卵泡抑素表达以及糖原合成酶激酶-3β的失活磷酸化，而这些参数不受曲古抑菌素A影响。然而，两种药物均无法抵消肌肉萎缩或泛素连接酶的过度表达。因此，仅调节肌肉生长抑制素/卵泡抑素轴似乎不足以纠正癌症恶病质中的肌肉萎缩。
