| First Author | Perry MC | Year | 2014 |
| Journal | Mol Endocrinol | Volume | 28 |
| Issue | 12 | Pages | 2060-71 |
| PubMed ID | 25361393 | Mgi Jnum | J:218270 |
| Mgi Id | MGI:5617100 | Doi | 10.1210/me.2014-1281 |
| Citation | Perry MC, et al. (2014) Estrogen-related receptor-alpha coordinates transcriptional programs essential for exercise tolerance and muscle fitness. Mol Endocrinol 28(12):2060-71 |
| abstractText | Muscle fitness is an important determinant of health and disease. However, the molecular mechanisms involved in the coordinate regulation of the metabolic and structural determinants of muscle endurance are still poorly characterized. Herein, we demonstrate that estrogen-related receptor alpha (ERRalpha, NR3B1) is essential for skeletal muscle fitness. Notably, we show that ERRalpha-null animals are hypoactive and that genetic or therapeutic disruption of ERRalpha in mice results in reduced exercise tolerance. Mice lacking ERRalpha also exhibited lactatemia at exhaustion. Gene expression profiling demonstrates that ERRalpha plays a key role in various metabolic processes important for muscle function including energy substrate transport and use (Ldhd, Slc16a1, Hk2, and Glul), the tricarboxylic acid cycle (Cycs, and Idh3g), and oxidative metabolism (Pdha1, and Uqcrq). Metabolomics studies revealed impairment in replenishment of several amino acids (eg, glutamine) during recovery to exercise. Moreover, loss of ERRalpha was found to alter the expression of genes involved in oxidative stress response (Hmox1), maintenance of muscle fiber integrity (Trim63, and Hspa1b), and muscle plasticity and neovascularization (Vegfa). Taken together, our study shows that ERRalpha plays a key role in directing transcriptional programs required for optimal mitochondrial oxidative potential and muscle fitness, suggesting that modulation of ERRalpha activity could be used to manage metabolic myopathies and/or promote the adaptive response to physical exercise. |
