Background: Autophagy is a physiological self-eating process that can promote cell survival or activate cell death in eukaryotic cells. In skeletal muscle, it is important in the maintenance of muscle mass and function that is critical to sustain mobility and regulate metabolism. UV radiation resistance-associated gene (UVRAG) regulates early stages of autophagy and autophagosome maturation, while also playing a key role in endosomal trafficking.
Methods: To determine the role of UVRAG in skeletal muscle in vivo, we generated muscle specific UVRAG knock-out mice using the cre-loxP system driven by Myf6 promoter that is exclusively expressed in skeletal muscle.
Results: Myf6 Cre+ UVRAGfl/fl (KO) mice were compared to littermate Myf6 Cre+ UVRAG+/+ (WT) controls under basal (normal chow diet) and HFD (high-fat diet) conditions. KO mice developed accelerated sarcopenia and impaired muscle function compared to WT littermates with aging on chow diet or on HFD. Interestingly, these mice displayed improved glucose tolerance and increased energy expenditure likely related to up-regulated FGF-21, a marker of muscle dysfunction. KO mice showed mitochondrial dysfunction, altered muscle mitochondrial morphology with increased mitochondrial fission, as well as EGFR accumulation reflecting defects in endosomal trafficking. To determine whether increased EGFR signaling had a causal role in muscle dysfunction, mice were treated with an EGFR inhibitor, Gefitinib, which partially restored markers of muscle and mitochondrial dysfunction. Conversely, constitutively active EGFR transgenic expression in UVRAG deficient muscle led to further detrimental effects with non-overlapping distinct defects in muscle function, with EGFR activation affecting muscle fiber type whereas UVRAG deficiency impaired mitochondrial homeostasis.
Conclusions: UVRAG and EGFR signaling together are critical in the maintenance of muscle mass and function with distinct mechanisms in the differentiation pathway.
M. Kim: None. D. Febbraro: None. M. Woo: None.
Canadian Institutes of Health Research; Kangbuk Samsung Hospital; Banting & Best Diabetes Centre