Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis
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 resistanc...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-05-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877821000259 |
| _version_ | 1818606303427166208 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Min Jeong Kim |
| collection | DOAJ |
| description | 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+ UVRAGfl/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. |
| first_indexed | 2024-12-16T14:08:43Z |
| format | Article |
| id | doaj.art-3ad65f38e4f146d3afd318e6c0762d84 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-16T14:08:43Z |
| publishDate | 2021-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-3ad65f38e4f146d3afd318e6c0762d842022-12-21T22:28:51ZengElsevierMolecular Metabolism2212-87782021-05-0147101185Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasisMin Jeong Kim0Daniella Febbraro1Sofia Farkona2Taylor Gillmore3Joe Eun Son4Romario Regeenes5Huntley H. Chang6Evan Pollock-Tahiri7Jiaqi Yang8Yoo Jin Park9Tharini Sivasubramaniyam10Soo Jung Oh11Punit Saraon12Igor Stagljar13Jonathan V. Rocheleau14Chi-Chung Hui15Isabella Caniggia16Zhenyu Hao17Tak W. Mak18Ana Konvalinka19Minna Woo20Toronto 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 KoreaToronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, CanadaToronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Multi-Organ Transplant Program, University Health Network, Toronto, ON M5G 1L7, CanadaLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, CanadaDevelopmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, CanadaToronto 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, CanadaToronto 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, CanadaToronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, CanadaToronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, CanadaToronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, CanadaToronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, CanadaToronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, CanadaDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, CanadaDonnelly 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, CanadaToronto 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, CanadaDevelopmental 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, CanadaLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, CanadaCampbell Family Cancer Research Institute, University Health Network, Toronto, ON M5G 2C1, CanadaCampbell Family Cancer Research Institute, University Health Network, Toronto, ON M5G 2C1, CanadaToronto 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, CanadaToronto 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; Corresponding author. Division of Nephrology, Department of Medicine, Toronto General Hospital, University Health Network, Toronto, ON M5G 1L7, Canada. Fax: +416 581 7880, Tel.: 416-581-7531.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+ UVRAGfl/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.http://www.sciencedirect.com/science/article/pii/S2212877821000259UVRAGSkeletal muscleFgf21Mitochondrial dynamicsEGFR |
| spellingShingle | 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 Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis Molecular Metabolism UVRAG Skeletal muscle Fgf21 Mitochondrial dynamics EGFR |
| title | Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis |
| title_full | Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis |
| title_fullStr | Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis |
| title_full_unstemmed | Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis |
| title_short | Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis |
| title_sort | distinct roles of uvrag and egfr signaling in skeletal muscle homeostasis |
| topic | UVRAG Skeletal muscle Fgf21 Mitochondrial dynamics EGFR |
| url | http://www.sciencedirect.com/science/article/pii/S2212877821000259 |
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