Mechanisms of Muscle Damage: Analysis of the Myotube Response to the Cancer Derived-Secretome

Abstract

Cancer cachexia is a complex paraneoplastic syndrome affecting up to 80% of advanced cancer patients and directly contributes to up to 30% of cancer related deaths. Cancer cachexia is characterized by the loss of skeletal muscle mass and systemic inflammation. It is a complex condition with many factors contributing to its onset and progression, many of which still need to be fully understood. Using an in vitro model of cancer cachexia, we demonstrate that in response to the cachectic cancer secretome, C2C12 myotubes upregulate the protein expression of proinflammatory cytokines and immune cell chemoattractants. Further, we observe an upregulation in inflammatory and immune response related genes, including Cxcl1 and Timp1 in the treated myotubes. These results implicate myofibers as key contributors to the inflammatory muscle environment in cachexia and suggest that immune cells, specifically neutrophils, may be recruited to the muscle environment and contribute to the progression of cachexia. Interestingly, both the LLC and MC38 cancer models have different cachectic phenotypes in vitro and in vivo, suggesting different mechanisms of muscle wasting in different cancer models, highlighting the diversity of the cachectic phenotype. We also show that the cachectic cancer secretome does not directly cause myotube membrane damage, suggesting that the muscle damage observed in cachexia is not a result of tumor derived factors and rather due to other cell interactions occurring in vivo.