Amiloride ameliorates muscle wasting in cancer cachexia through inhibiting tumor-derived exosome release

作者：Lin Zhou, Tong Zhang, Wei Shao, Ruohan Lu, Lin Wang, Haisheng Liu, Bin Jiang, Shiqin Li, Huiqin Zhuo, Su-Heng Wang, Qinxi Li, Caihua Huang, Donghai Lin · 发表于：Skeletal Muscle · 年份：2021 · DOI：10.1186/s13395-021-00274-5 · 被引用次数：44 · 研究领域：Muscle Physiology and Disorders、Nutrition and Health in Aging、Extracellular vesicles in disease

BACKGROUND: Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of the amiloride treatment for ameliorating muscle wasting in murine models of cancer cachexia. METHODS: The CT26 and LLC tumor cells were subcutaneously injected into mice to induce colon cancer cachexia and lung cancer cachexia, respectively. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 model and the LLC model were separately characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. RESULTS: The CT26 and LLC cachexia models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue, and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affect...