Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity
Year: 2023
Type: article
Abstract: Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Genetic evidence indicates that the orphan nuclear receptors estrogen receptor-related receptors (ERRs) play an important role in skeletal muscle exercise capacity. Three ERR subtypes exist (ERRα, β, and γ), and although ERRβ/γ agonists have been designed, there have been significant difficulties in designing compounds with ERRα agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs in vivo . Here, we report the identification of a synthetic ERR pan agonist, SLU-PP-332, that targets all three ERRs but has the highest potency for ERRα. Additionally, SLU-PP-332 has sufficient pharmacokinetic properties to be used as an in vivo chemical tool. SLU-PP-332 increases mitochondrial function and cellular respiration in a skeletal muscle cell line. When administered to mice, SLU-PP-332 increased the type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. We also observed that SLU-PP-332 induced an ERRα-specific acute aerobic exercise genetic program, and the ERRα activation was critical for enhancing exercise endurance in mice. These data indicate the feasibility of targeting ERRα for the development of compounds that act as exercise mimetics that may be effective in the treatment of numerous metabolic disorders and to improve muscle function in the aging.
Source: ACS Chemical Biology
Authors: Cyrielle Billon, Sadichha Sitaula, Subhashis Banerjee, Ryan Welch, Bahaa Elgendy, Lamees Hegazy, Tae Gyu Oh, Melissa Kazantzis, Arindam Chatterjee, John Chrivia, Matthew E. Hayes, Weiyi Xu, Angelica Hamilton, Janice M. Huss, Lilei Zhang, John K. Walker, Michael Downes, Ronald M. Evans, Thomas P. Burris
Institutions: University of Health Sciences and Pharmacy, Washington University in St. Louis, Saint Louis University, Salk Institute for Biological Studies, Scripps Research Institute, University of Florida, Baylor College of Medicine, City Of Hope National Medical Center, City of Hope, Howard Hughes Medical Institute
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, American Diabetes Association, March of Dimes Foundation, Leona M. and Harry B. Helmsley Charitable Trust, Saint Louis University, National Institutes of Health, Stand Up To Cancer, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1157786332, G1204134318, Development of RORalpha and RORgamma Ligands for Treatment of Behavioral Disorders, G129058862, G1453931010, G1820179381, G2063172648, G2064563154, G2085306070, G2147928738, G2506757200, G2659625731, G303972377, DETECTION AND MODELS OF TOXICANT EXPOSURE, G352863456, G3648063599, G3812021946, Spatial Regulation of Developmental Gene Expression, G637574655, Exercise Mimetics for Dementia and Alzheimer's Disease, G7661236236, G7673286369, G7715059201, G827344990, G8726977943, G9000076190, G9000105172, G9000195585, G9000241332, G9000265946
OpenAlex ID: W4361282845