Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia

Rulin Sun, Santao Zhang, Wenjun Hu, Xing Lu, Ning Lou, Zhende Yang, Shaoyong Chen, Xiaoping Zhang, Hongmei Yang
2016 American Journal of Physiology - Cell Physiology  
45 Muscle wasting is the hallmark of cancer cachexia and is associated with poor 46 quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase 47 (HDAC) inhibitor, has important biological effects in the treatment of muscular 48 dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer 49 cachexia, we explored the role of VPA in two cancer cachectic mouse models 50 [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and 51
more » ... rophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC 52 cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA 53 increased the mass and cross-sectional area (CSA) of skeletal muscles in 54 tumor-bearing (TB) mice. Furthermore, treatment with VPA also increased the 55 diameter of myotubes cultured in conditioned medium. The skeletal muscles in 56 cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of 57 CCAAT/enhancer binding protein beta (C/EBPβ), resulting in atrogin1 58 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. 59 Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via 60 activating the C/EBPβ-responsive cis-element and subsequently inhibited by VPA. In 61 contrast to the effect of VPA on the levels of C/EBPβ, the levels of inactivating 62 forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle 63 wasting and myotube atrophy and reduced C/EBPβ binding to atrogin1 promoter 64 locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might 65 be a promising new approach for the preservation of skeletal muscle in cancer 66 4 cachexia. 67 68 KEYWORDS 69 VPA; muscle wasting; cancer cachexia; C/EBPβ; atrogin1 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 5 89 Cachexia is a multifactorial syndrome associated with changes in many 90 metabolic pathways. The syndrome is characterized by weight loss at the expense of 91 skeletal muscle and body fat (3). Muscle wasting is a systemic response to various 92 diseases, including cancer, sepsis, renal and cardiac failure, and Acquired Immune 93 Deficiency Syndrome (AIDS) (11, 23). Millions of new cancer cases and cancer 94 deaths occur worldwide (54), and more than 50% of cancer patients suffer from 95 cancer cachexia, which is often accompanied by progressive atrophy of skeletal 96 muscle (52). 97 In cancer cachexia, multiple factors can influence muscle mass, such as 98 proteolysis-inducing factor, glucocorticoids, tumor necrosis factor, interleukin-6, and 99 angiotensin II (53). Many of these factors induce muscle wasting by altering protein 100 metabolism via protein synthesis and degradation pathways in muscle cells (28).
doi:10.1152/ajpcell.00344.2015 pmid:27122162 fatcat:gjbbmigahzbbfmiqigk5zvgbrq