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Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis

التفاصيل البيبلوغرافية
العنوان: Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis
المؤلفون: Tak W. Mak, Punit Saraon, Joe Eun Son, Jiaqi Yang, Zhenyu Hao, Huntley H. Chang, Taylor Gillmore, Minna Woo, Min Jeong Kim, Romario Regeenes, Yoo Jin Park, Daniella Febbraro, Chi-chung Hui, Isabella Caniggia, Soo Jung Oh, Sofia Farkona, Igor Stagljar, Tharini Sivasubramaniyam, Ana Konvalinka, Evan Pollock-Tahiri, Jonathan V. Rocheleau
المصدر: Molecular Metabolism, Vol 47, Iss, Pp 101185-(2021)
Molecular Metabolism
بيانات النشر: Elsevier, 2021.
سنة النشر: 2021
مصطلحات موضوعية: 0301 basic medicine, Male, Programmed cell death, Fgf21, Ultraviolet Rays, Autophagosome maturation, EGFR, Skeletal muscle, 030209 endocrinology & metabolism, UVRAG, Endosomes, Mitochondrion, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Autophagy, Animals, Homeostasis, Muscle, Skeletal, Molecular Biology, Internal medicine, Mice, Knockout, Chemistry, Tumor Suppressor Proteins, Cell Biology, medicine.disease, RC31-1245, Cell biology, ErbB Receptors, Fibroblast Growth Factors, 030104 developmental biology, medicine.anatomical_structure, Sarcopenia, Mitochondrial dynamics, Mitochondrial fission, Female, Original Article, Transcriptome
الوصف: 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.
Highlights • Deletion of UVRAG in skeletal muscle accelerates muscle wasting with aging. • UVRAG in skeletal muscle regulates mitochondrial dynamics and function. • UVRAG deletion leads to EGFR accumulation in skeletal muscle. • Constitutively active EGFR contributes to muscle fiber type determination.
اللغة: English
تدمد: 2212-8778
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::653e913566868262ca69abf944c92d82
http://www.sciencedirect.com/science/article/pii/S2212877821000259
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....653e913566868262ca69abf944c92d82
قاعدة البيانات: OpenAIRE
الوصف
تدمد:22128778