Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia
| Autor: | Zhende Yang, Rulin Sun, Xiaoping Zhang, Shaoyong Chen, Xing Lu, Ning Lou, Santao Zhang, Hongmei Yang, Wenjun Hu |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Cachexia Time Factors Physiology Muscle Fibers Skeletal Down-Regulation Muscle Proteins Adenocarcinoma Biology Carcinoma Lewis Lung 03 medical and health sciences Atrophy Cell Line Tumor Internal medicine Enhancer binding medicine Animals RNA Messenger Muscular dystrophy Muscle Skeletal Promoter Regions Genetic Binding Sites SKP Cullin F-Box Protein Ligases Dose-Response Relationship Drug Myogenesis CCAAT-Enhancer-Binding Protein-beta Valproic Acid Lewis lung carcinoma Skeletal muscle Cell Biology medicine.disease Histone Deacetylase Inhibitors Mice Inbred C57BL Muscular Atrophy 030104 developmental biology Endocrinology medicine.anatomical_structure Culture Media Conditioned Colonic Neoplasms Proteolysis FOXO3 Female lipids (amino acids peptides and proteins) Signal Transduction |
| Zdroj: | American Journal of Physiology-Cell Physiology. 311:C101-C115 |
| ISSN: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.00344.2015 |
| Popis: | Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by 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)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor-bearing 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/EBPβ), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPβ-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPβ, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPβ binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia. |
| Databáze: | OpenAIRE |
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