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

Cancer Research
Sarah M JudgeAndrew R Judge

Abstract

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 no...Continue Reading

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Citations

Nov 21, 2020·Journal of Neuromuscular Diseases·Stefano SchiaffinoBert Blaauw
Feb 3, 2021·Journal of Cachexia, Sarcopenia and Muscle·Daria NeyroudAndrew R Judge
Feb 19, 2021·Frontiers in Genetics·Dongjun DaiQichun Wei
Aug 14, 2021·The Journal of Biological Chemistry·Athéna C Patterson-OrazemRaquel L Lieberman
Aug 18, 2021·Experimental Eye Research·Mackenzie D MartinRaquel L Lieberman

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