Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis

Min Jeong Kim; Daniella Febbraro; Sofia Farkona; Taylor Gillmore; Joe Eun Son; Romario Regeenes; Huntley H Chang; Evan Pollock-Tahiri; Jiaqi Yang; Yoo Jin Park; Tharini Sivasubramaniyam; Soo Jung Oh; Punit Saraon; Igor Stagljar; Jonathan V Rocheleau; Chi-Chung Hui; Isabella Caniggia; Zhenyu Hao; Tak W Mak; Ana Konvalinka; Minna Woo

doi:10.1016/j.molmet.2021.101185

Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis

Mol Metab. 2021 May:47:101185. doi: 10.1016/j.molmet.2021.101185. Epub 2021 Feb 6.

Authors

Min Jeong Kim¹, Daniella Febbraro², Sofia Farkona³, Taylor Gillmore⁴, Joe Eun Son⁵, Romario Regeenes⁶, Huntley H Chang⁶, Evan Pollock-Tahiri⁷, Jiaqi Yang⁷, Yoo Jin Park⁷, Tharini Sivasubramaniyam⁷, Soo Jung Oh⁷, Punit Saraon⁸, Igor Stagljar⁹, Jonathan V Rocheleau¹⁰, Chi-Chung Hui¹¹, Isabella Caniggia⁴, Zhenyu Hao¹², Tak W Mak¹², Ana Konvalinka¹³, Minna Woo¹⁴

Affiliations

¹ Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, South Korea.
² Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
³ Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Multi-Organ Transplant Program, University Health Network, Toronto, ON M5G 1L7, Canada.
⁴ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.
⁵ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁶ Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
⁷ Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
⁸ Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁹ Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada; Departments of Biochemistry and Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁰ Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹¹ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹² Campbell Family Cancer Research Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
¹³ Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Multi-Organ Transplant Program, University Health Network, Toronto, ON M5G 1L7, Canada; Division of Nephrology, Department of Medicine, Toronto General Hospital, University Health Network, Toronto, ON M5G 1L7, Canada.
¹⁴ Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University Health Network and Sinai Health System, University of Toronto, Toronto, ON M5G 2C4, Canada. Electronic address: mwoo@uhnresearch.ca.

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.

Keywords: EGFR; Fgf21; Mitochondrial dynamics; Skeletal muscle; UVRAG.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy
Endosomes / metabolism
ErbB Receptors / genetics
ErbB Receptors / metabolism*
Female
Fibroblast Growth Factors / metabolism
Homeostasis*
Male
Mice
Mice, Knockout
Mitochondrial Dynamics
Muscle, Skeletal / metabolism*
Transcriptome
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Ultraviolet Rays

Substances

Tumor Suppressor Proteins
fibroblast growth factor 21
Fibroblast Growth Factors
EGFR protein, mouse
ErbB Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding