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Mol Endocrinol. 2014 Dec;28(12):2060-71. doi: 10.1210/me.2014-1281.

Estrogen-related receptor-α coordinates transcriptional programs essential for exercise tolerance and muscle fitness.

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Goodman Cancer Research Centre (M.-C.P., C.R.D., I.S.T., W.B., V.G.), McGill University, Montréal, Québec, H3A 1A3, Canada; and Departments of Biochemistry (M.-C.P., V.G.), Medicine (I.S.T., V.G.), and Oncology (V.G.), McGill University, Montréal, Québec H3G 1Y6, Canada.


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 α (ERRα, NR3B1) is essential for skeletal muscle fitness. Notably, we show that ERRα-null animals are hypoactive and that genetic or therapeutic disruption of ERRα in mice results in reduced exercise tolerance. Mice lacking ERRα also exhibited lactatemia at exhaustion. Gene expression profiling demonstrates that ERRα 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 ERRα 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 ERRα plays a key role in directing transcriptional programs required for optimal mitochondrial oxidative potential and muscle fitness, suggesting that modulation of ERRα activity could be used to manage metabolic myopathies and/or promote the adaptive response to physical exercise.

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