Ashwin Mathew

Background: Physical fitness and exercise capacity are important predictors of lifespan and metabolic health. Engaging in consistent physical activity is found to improve metabolic health, and poor physical fitness combined with inactivity are risk factors for various chronic diseases, such as type II diabetes, obesity, and cardiovascular diseases.¹ Estrogen-related receptors (ERRs) are a subset of orphan nuclear receptors that have emerged as key regulators of mitochondrial biogenesis, oxidative metabolism, and skeletal muscle vascularization, all of which are processes that are central to physical endurance and the tolerance to exercise.^1,5 Among them, ERRɑ and ERRγ are prominently expressed in skeletal muscle, and are hypothesized to regulate metabolic flexibility and muscle adaptation in response to physiological stressors.^2,3 The loss of these receptors impairs mitochondrial function and oxidative capacity, highlighting their potential as therapeutic targets for improving muscular and metabolic health.

Objective: In this narrative review, we evaluate the physiological roles of ERRɑ and ERRγ in regulating exercise-induced adaptations in skeletal muscle and explore their potential therapeutic applications in addressing fatigue and ischemic injury.

Search Methods: An online search in the PubMed database was conducted from 2017-2024 using the following MeSH and/or keywords: “estrogen-related receptors”, “skeletal muscle”, “exercise intolerance”, and “exercise capacity”.

Results: In mouse models, muscle-specific deletion of ERRɑ and ERRγ resulted in significantly impaired oxidative phosphorylation and mitochondrial biogenesis in both glycolytic and oxidative muscle types.^1,5 These double knockout (KO) mice exhibited pale musculature, reduced treadmill endurance, elevated lactate levels, and failed to upregulate oxygen consumption during exertion, indicating metabolic inflexibility.¹ ERRɑ overexpression in ischemic skeletal muscle led to increased oxidative myofibers, capillary, and vascular endothelial growth factor (VEGF) expression, promoting muscle revascularization and recovery after hindlimb ischemia.² Similarly, ERRγ gene therapy using AAV9 delivery enhanced vascularization and accelerated myofiber regeneration following ischemic injury.³ Muscles receiving AAV9 delivery had higher ERRγ expression, and showed increased mitochondrial content, redder appearance, and improved blood perfusion.³ The administration of SLU-PP-332, a pan-ERR agonist with high selectivity for ERRɑ, induced the expression of oxidative genes, mitochondrial proteins, and endurance-related exercise adaptation transcript DDIT4.⁴ Mice treated with SLU-PP-332 exhibited stronger grip, a 70% longer run time and a 45% increase in distance traveled on treadmill tests, suggesting the agonist’s ability to increase exercise endurance. Mice with specific deletions of these SLU activated receptors were resistant to improved performance under conditions of fatigue.

Conclusion: ERRɑ and ERRγ are indispensable for exercise tolerance, mitochondrial activity, oxidative gene expression, and muscle vascularization. Therapeutically targeting these receptors in the future, whether by transgenic overexpression, gene therapy, or synthetic agonist, could potentially enhance skeletal muscle endurance, facilitate post-ischemic recovery, and improve metabolic flexibility.^2,3,4,5 Future research could include advancing ERR-based gene therapies and synthetic agonists to clinical trials for populations where exercise tolerance is limited, or recovery from vascular injury is impaired, and in the future, in trials for metabolic and vascular diseases, such as sarcopenia, PAD, or muscular dystrophy. Continued development of these therapies could provide novel treatment avenues for metabolic and neuromuscular diseases in the future.

Works Cited:

1. Wattez JS, Eury E, Hazen BC, et al. Loss of skeletal muscle estrogen-related receptors leads to severe exercise intolerance. Molecular Metabolism. 2023;68:101670. doi:10.1016/j.molmet.2023.101670
2. Sopariwala DH, Likhite N, Pei G, et al. Estrogen‐related receptor α is involved in angiogenesis and skeletal muscle revascularization in hindlimb ischemia. The FASEB Journal. 2021; 35:e21480. doi:10.1096/fj.202001794RR
3. Sopariwala DH, Rios AS, Saley A, Kumar A, Narkar VA. Estrogen‐Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis and Muscle Recovery in Preclinical Model of PAD. Journal of the American Heart Association. 2023;12(16):e028880. doi:10.1161/JAHA.122.028880
4. Billon C, Sitaula S, Banerjee S, et al. Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity. ACS Chem Biol. 2023;18(4):756-771. doi:10.1021/acschembio.2c00720
5. Sopariwala DH, Rios AS, Pei G, et al. Innately expressed estrogen-related receptors in the skeletal muscle are indispensable for exercise fitness. The FASEB Journal. 2023;37(2):e22727. doi:10.1096/fj.202201518R