MEF2c-dependent downregulation of Myocilin mediates cancer-induced muscle wasting and associates with cachexia in cancer patients

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared to wild type mice-thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Further, we identified the Myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain-of-function significantly deterred cancer-induced muscle wasting and dysfunction in a pre-clinical model of pancreatic ductal adenocarcinoma (PDAC). Lastly, compared to non-cancer control patients MYOC was significantly reduced in skeletal muscle of PDAC patients defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of cachectic cancer patients.