The Manifestation Of Muscle Wasting Induced By Cancer In Different Stages And The Mechanism Underlying Attenuating Muscle Wasting By Valproic Acid

Background:Cancer cachexia is one of the most significant side effects of many types of tumors. Muscle wasting, which commonly occurs in cancer cachexia, is a progressive metabolic disorder that results in loss of muscle. It is characterized by impaired quality of life and poor patient survival. At present, no satisfactory clinical therapy is available for treating cancer-induced muscle wasting. To identify an appropriate treatment, research on the mechanism underlying muscle wasting is essential.Thus far, studies on muscle wasting using cancer cachexia models have generally focused on early cancer cachexia (ECC), before severe body weight loss occurs. And people have known little about muscle wasting in late cancer cachexia.Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. So it should also have the potential to attenuate skeletal muscle wasting induced by cancer.Part ? Comparative Molecular Analysis of Early and Late Cancer Cachexia-Induced Muscle Wasting in Mouse ModelsPurpose:In this study, our aim was to comprehensively analyze the expression of a group of molecules involved in muscle wasting during different stages of cancer cachexia.Methods:For the better understanding of the molecular mechanisms involved in muscle wasting in cancer cachexia, we chose two different cancer cachexia models for this study:the C26 adenocarcinoma-induced cancer cachexia model (C26 model) and the Lewis lung carcinoma-induced cancer cachexia model (LLC model). In each model, tumor bearing (TB) and control (CN) mice were injected with cancer cells (C26 cells or LLC cells) and PBS, respectively. The mice were euthanized on the 24th day (the TB and CN mice were defined as the ECC and EC-CN mice, respectively) or the 36th day (the TB and CN mice were defined as the LCC and LCC-CN mice, respectively) after injection, and then tissues were harvested and analyzed.Results:Both the ECC and LCC mice developed cancer cachexia, as determined by decreased tumor-free body masses, adipose masses and skeletal muscle masses compared with their matched controls for the two models. The amounts of muscle loss differed between the ECC and LCC mice. In addition, the expression of some molecules was altered in the muscles from the LCC mice but not in those from the ECC mice compared with the CN mice. Further, the alterations in the expression of several molecules in muscle differed between the C26 and LCC models.Conclusion:Although the ECC and LCC mice shared some common manifestations and molecular mechanisms in muscle wasting, the molecules with altered expression in these two groups of mice were not exactly the same. These findings may provide a solid basis for the research and development of a therapeutic target for muscle wasting in cancer cachexia for preventing progression to the late stage.Part ? Valproic Acid Attenuates Skeletal Muscle Wasting by Inhibiting C/EBP?-regulated Atroginl Expression in Cancer CachexiaPurpose:The purpose of this study was to verify whether VPA could ameliorate muscle wasting induced by cancer.Methods:We explored the role of VPA in two cancer cachectic mouse models (colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)) and atrophied C2C12 myotubes (induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)).Results:Our data demonstrated that treatment with VPA increased the mass and cross-sectional area (CSA) of skeletal muscles in tumor bearing (TB) mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBP?), resulting in atroginl downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atroginl promoter activity in myotubes was stimulated by CCM via activating the C/EBP?-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBP?, the levels of inactivating forkhead box 03 (Fox03a) were unaffected.Conclusion:In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBP? binding to the C/EBP?-binding motif in the atroginl promoter in myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia.