Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron–sulfur cluster depletion in human skeletal muscle
| Autor: | Chuming Chen, Cathy H. Wu, Suh Young Jeong, Ronald G. Haller, Sun Young Park, Hongzhan Huang, Thanemozhi G. Natarajan, Wing Hang Tong, Daniel R. Crooks, Tracey A. Rouault, Manik C. Ghosh |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Hydroxymethylglutaryl-CoA Synthase Iron-Sulfur Proteins Male Muscle tissue medicine.medical_specialty Respiratory chain Mitochondrion Muscular Diseases Mitochondrial myopathy Internal medicine Genetics medicine Humans Muscle Skeletal Myopathy Molecular Biology Cells Cultured Genetics (clinical) Aged biology Myogenesis Skeletal muscle Articles General Medicine Middle Aged medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Mitochondria Muscle Fibroblast Growth Factors medicine.anatomical_structure Endocrinology Gene Expression Regulation Case-Control Studies biology.protein Acidosis Lactic Female ISCU medicine.symptom Energy Metabolism Transcription Factors |
| Zdroj: | Human Molecular Genetics. 23:24-39 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddt393 |
| Popis: | Iron –s ulfur (Fe-S) clusters are ancient enzyme cofactors found in virtually all life forms. We evaluated the physiological effects of chronic Fe-S cluster deficiency in human skeletal muscle, a tissue that relies heavily on Fe-S cluster-mediated aerobic energy metabolism. Despite greatly decreased oxidative capacity, muscle tissue from patients deficient in the Fe-S cluster scaffold protein ISCU showed a predominance of type I oxidative muscle fibers and higher capillary density, enhanced expression of transcriptional co-activator PGC-1a and increased mitochondrial fatty acid oxidation genes. These Fe-S cluster-deficient muscles showed a dramatic up-regulation of the ketogenic enzyme HMGCS2 and the secreted protein FGF21 (fibroblast growth factor 21). Enhanced muscle FGF21 expression was reflected by elevated circulating FGF21 levels in the patients, and robust FGF21 secretion could be recapitulated by respiratory chain inhibition in cultured myotubes. Our findings reveal that mitochondrial energy starvation elicits a coordinated response in Fe-S-deficient skeletal muscle that is reflected systemically by increased plasma FGF21 levels. |
| Databáze: | OpenAIRE |
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