Thyroid Hormone Receptor α Regulates Autophagy, Mitochondrial Biogenesis, and Fatty Acid Use in Skeletal Muscle
| Autor: | Xuguang Zhu, Rohit A. Sinha, Jia Pei Ho, Paul M. Yen, Cho Rong Han, Karine Gauthier, Sheue-yann Cheng, Andrea Lim, Jin Zhou |
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| Přispěvatelé: | Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine muscle Endocrinology Diabetes and Metabolism [SDV]Life Sciences [q-bio] Cathepsin D Bioinformatics Cathepsin B MESH: Hypothyroidism Mice 0302 clinical medicine Endocrinology TRα1 mutation lipid metabolism MESH: Animals Receptor Research Articles MESH: Lipid Metabolism MESH: Muscle Skeletal Chemistry MESH: Energy Metabolism Mitochondrial Turnover MESH: Mitochondrial Turnover Cell biology medicine.anatomical_structure Thyroid Hormone Receptors alpha medicine.medical_specialty autophagy MESH: Mutation Skeletal muscle weakness MEDLINE MESH: Thyroid Hormone Receptors alpha 030209 endocrinology & metabolism 03 medical and health sciences Hypothyroidism mitochondrial function Internal medicine medicine Animals Humans MESH: Autophagy Muscle Skeletal MESH: Mice Thyroid hormone receptor business.industry Autophagy Skeletal muscle TFAM MESH: Male 030104 developmental biology Mitochondrial biogenesis Mutation Energy Metabolism business |
| Zdroj: | Endocrinology Endocrinology, 2021, 162 (9), ⟨10.1210/endocr/bqab112⟩ Endocrinology, Endocrine Society, 2021, 162 (9), ⟨10.1210/endocr/bqab112⟩ |
| ISSN: | 0013-7227 |
| DOI: | 10.1210/endocr/bqab112⟩ |
| Popis: | Skeletal muscle (SM) weakness occurs in hypothyroidism and resistance to thyroid hormone α (RTHα) syndrome. However, the cell signaling and molecular mechanism(s) underlying muscle weakness under these conditions is not well understood. We thus examined the role of thyroid hormone receptor α (TRα), the predominant TR isoform in SM, on autophagy, mitochondrial biogenesis, and metabolism to demonstrate the molecular mechanism(s) underlying muscle weakness in these two conditions. Two genetic mouse models were used in this study: TRα1PV/+ mice, which express the mutant Thra1PV gene ubiquitously, and SM-TRα1L400R/+ mice, which express TRα1L400R in a muscle-specific manner. Gastrocnemius muscle from TRα1PV/+, SM-TRα1L400R/+, and their control mice was harvested for analyses. We demonstrated that loss of TRα1 signaling in gastrocnemius muscle from both the genetic mouse models led to decreased autophagy as evidenced by accumulation of p62 and decreased expression of lysosomal markers (lysosomal-associated membrane protein [LAMP]-1 and LAMP-2) and lysosomal proteases (cathepsin B and cathepsin D). The expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial transcription factor A (TFAM), and estrogen-related receptor α (ERRα), key factors contributing to mitochondrial biogenesis as well as mitochondrial proteins, were decreased, suggesting that there was reduced mitochondrial biogenesis due to the expression of mutant TRα1. Transcriptomic and metabolomic analyses of SM suggested that lipid catabolism was impaired and was associated with decreased acylcarnitines and tricarboxylic acid cycle intermediates in the SM from the mouse line expressing SM-specific mutant TRα1. Our results provide new insight into TRα1-mediated cell signaling, molecular, and metabolic changes that occur in SM when TR action is impaired. |
| Databáze: | OpenAIRE |
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