Mechanisms of chemotherapy?induced muscle wasting in mice with cancer cachexia

Background Cachexia is a debilitating complication of cancer characterized by progressive wasting and weakness skeletal muscles that reduces quality life can compromise survival. Many anticancer treatments, such as chemotherapy, also cause muscle wasting, which impairs the response to treatment. Given many patients present with cachexia at initiation treatment, we investigated whether cachectic mice were susceptible chemotherapy-induced investigate contributing mechanisms, including dysregulation microRNAs (miRs). Methods Cachectic colon-26 (C-26) tumour-bearing given 5-fluourouracil (5-FU) chemotherapy or vehicle treatment analysed for mass, fibre size composition, miR expression. Mechanisms validated in vitro using C2C12 cell culture mimics inhibitors confirmed vivo injecting 5-FU-treated recombinant adeno-associated viral (rAAV) vectors encoding sponge. Results In mice, 5-FU exacerbated loss mass compared (by ?12% ?20%, P < 0.05). expression profiling, quantitative real-time PCR, analyses revealed mechanisms miR-351-3p-dependent ERK2 inhibition. Intramuscular injection rAAV sponge reduce miR-351-3p enhanced ERK phosphorylation (+18%, 0.05) increased (+15%, 0.01). Hsa-miR-125a-3p shares similar predicted gene targets mmu-miR-351-3p, its inhibition human cells prevented 5-FU-induced atrophy (P 0.001) 0.001). Conclusions The findings implicate miR-351-3p-mediated mechanism promising adjunct therapy preserving during