Dataset Information

Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis.

ABSTRACT:

Objective

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 for maintaining muscle mass and function that is critical to sustain mobility and regulate metabolism. The UV radiation resistance-associated gene (UVRAG) regulates the early stages of autophagy and autophagosome maturation and plays a key role in endosomal trafficking. This study investigated the essential in vivo role of UVRAG in skeletal muscle biology.

Methods

To determine the role of UVRAG in skeletal muscle in vivo, we generated muscle-specific UVRAG knockout mice using the Cre-loxP system driven by Myf6 promoter that is exclusively expressed in skeletal muscle. Myf6-Cre⁺ UVRAG^fl/fl (M-UVRAG^-/-) mice were compared to littermate Myf6-Cre⁺ UVRAG^+/+ (M-UVRAG^+/+) controls under basal conditions on a normal chow diet. Body composition, muscle function, and mitochondria morphology were assessed in muscles of the WT and KO mice at 24 weeks of age.

Results

M-UVRAG^-/- mice developed accelerated sarcopenia and impaired muscle function compared to M-UVRAG^+/+ littermates at 24 weeks of age. Interestingly, these mice displayed improved glucose tolerance and increased energy expenditure likely related to upregulated Fgf21, a marker of muscle dysfunction. Skeletal muscle of the M-UVRAG^-/- mice showed altered mitochondrial morphology with increased mitochondrial fission and EGFR accumulation reflecting defects in endosomal trafficking. To determine whether increased EGFR signaling had a causal role in muscle dysfunction, the mice were treated with an EGFR inhibitor, gefitinib, which partially restored markers of muscle and mitochondrial deregulation. 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 the muscle fiber type whereas UVRAG deficiency impaired mitochondrial homeostasis.

Conclusions

Our results show that both UVRAG and EGFR signaling are critical for maintaining muscle mass and function with distinct mechanisms in the differentiation pathway.

SUBMITTER: Kim MJ

PROVIDER: S-EPMC7921879 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis.

Kim Min Jeong MJ Febbraro Daniella D Farkona Sofia S Gillmore Taylor T Son Joe Eun JE Regeenes Romario R Chang Huntley H HH Pollock-Tahiri Evan E Yang Jiaqi J Park Yoo Jin YJ Sivasubramaniyam Tharini T Oh Soo Jung SJ Saraon Punit P Stagljar Igor I Rocheleau Jonathan V JV Hui Chi-Chung CC Caniggia Isabella I Hao Zhenyu Z Mak Tak W TW Konvalinka Ana A Woo Minna M

Molecular metabolism 20210206

<h4>Objective</h4>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 for maintaining muscle mass and function that is critical to sustain mobility and regulate metabolism. The UV radiation resistance-associated gene (UVRAG) regulates the early stages of autophagy and autophagosome maturation and plays a key role in endosomal trafficking. This study investigated the essential in vivo role ...[more]

PMID: 33561544

Similar Datasets

Project description:Muscle wasting in cancer cachexia can be alleviated by blocking activin receptor type 2 (ACVR2) ligands through changes in protein synthesis/degradation. These changes in cellular and protein metabolism may alter protein homeostasis. First, we elucidated the acute (1-2 days) and 2-week effects of blocking ACVR2 ligands by soluble activin receptor 2B (sACVR2B-Fc) on unfolded protein response (UPR), heat shock proteins (HSPs) and redox balance in a healthy mouse skeletal muscle. Second, we examined UPR, autophagy and redox balance with or without sACVR2B-Fc administration in muscle and liver of C26 tumor-bearing mice. The indicators of UPR and HSPs were not altered 1-2 days after a single sACVR2B-Fc administration in healthy muscles, but protein carbonyls increased (p < 0.05). Two weeks of sACVR2B-Fc administration increased muscle size, which was accompanied by increased UPR markers: GRP78 (p < 0.05), phosphorylated eIF2? (p < 0.01) and HSP47 (p < 0.01). Additionally, protein carbonyls and reduced form of glutathione increased (GSH) (p < 0.05). On the other hand, C26 cancer cachexia manifested decreased UPR markers (p-eIF2?, HSP47, p-JNK; p < 0.05) and antioxidant GSH (p < 0.001) in muscle, whereas the ratio of oxidized to reduced glutathione increased (GSSG/GSH; p < 0.001). Administration of sACVR2B-Fc prevented the decline in GSH and increased some of the UPR indicators in tumor-bearing mice. Additionally, autophagy markers LC3II/I (p < 0.05), Beclin-1 (p < 0.01), and P62 (p < 0.05) increased in the skeletal muscle of tumor-bearing mice. Finally, indicators of UPR, PERK, p-eIF2? and GRP78, increased (p < 0.05), whereas ATF4 was strongly decreased (p < 0.01) in the liver of tumor-bearing mice while sACVR2B-Fc had no effect. Muscle GSH and many of the altered UPR indicators correlated with tumor mass, fat mass and body mass loss. In conclusion, experimental cancer cachexia is accompanied by distinct and tissue-specific changes in proteostasis. Muscle hypertrophy induced by blocking ACVR2B ligands may be accompanied by the induction of UPR and increased protein carbonyls but blocking ACVR2B ligands may upregulate antioxidant protection.

Dataset Information

Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis.

Objective

Methods

Results

Conclusions

Publications

Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets