Paracrine effects of cancer on skeletal muscle: myosin loss and mitochondrial dysfunction (1163.10)

Abstract

Cancer cachexia is a severe skeletal muscle wasting syndrome directly responsible for 30% of all cancer deaths. Cancer exerts paracrine effects on skeletal muscle that trigger myosin loss and metabolic dysfunction. Clinical trials using cyclooxygenase 2 (COX2) inhibitors to treat cachexia had some success. Therefore, we hypothesized that tumor‐induced COX2 expression contributes to myosin loss and mitochondrial dysfunction. We incubated C2C12 myotubes with control or Lewis lung carcinoma conditioned medium (LLCCM) for 48hr. We measured protein content by western blot, and oxygen consumption rate (OCR) of intact myotubes using a Seahorse XF24. Protein content is presented as means±SD in arbitrary units (n=6/group, t test). OCR is presented in pmoles O2/min (n=8/group, repeated measures ANOVA). LLCCM treatment decreased myosin content by 70%, from 7.2±2.7 to 2.1±1 AU (p<0.01), while COX2 content increased 75%, from 1.9 ±0.1 to 3.3 ±0.2 (p<0.001). There was no significant effect on mitochondrial complex content, p >0.05 for complexes I, III, IV and V. LLCCM decreased basal OCR by 30% (p<0.003), but did not alter leak or maximal uncoupled OCR. We found that LLCCM treatment induced myosin loss and impaired mitochondrial function in C2C12 myotubes, correlating with increased COX2 content. These data support our original hypothesis, and suggest that interventions that target COX2 may be useful for cancer cachexia.Grant Funding Source: Supported by Support: NIH AR055974 (FHA).