2. Academic Validation
  3. Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity

Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity

  • ACS Chem Biol. 2023 Apr 21;18(4):756-771. doi: 10.1021/acschembio.2c00720.
Cyrielle Billon 1,  Sadichha Sitaula 1,  Subhashis Banerjee 2,  Ryan Welch 3,  Bahaa Elgendy 1,  Lamees Hegazy 1,  Tae Gyu Oh 3,  Melissa Kazantzis 4,  Arindam Chatterjee 2,  John Chrivia 2,  Matthew E Hayes 5,  Weiyi Xu 6,  Angelica Hamilton 7,  Janice M Huss 7,  Lilei Zhang 6,  John K Walker 2 8,  Michael Downes 3,  Ronald M Evans 3 9,  Thomas P Burris 1 5
Affiliations

Affiliations

  • 1 Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, Missouri 63110, United States.
  • 2 Department of Pharmacology & Physiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, United States.
  • 3 Gene Expression Laboratory Salk Institute for Biological Studies, La Jolla, California 92037, United States.
  • 4 The Scripps Research Institute Jupiter, Jupiter, Florida 33458, United States.
  • 5 University of Florida Genetics Institute, Gainesville, Florida 32610, United States.
  • 6 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 7 Department of Molecular & Cellular Endocrinology, City of Hope, Duarte, California 91010, United States.
  • 8 Department of Chemistry, Saint Louis University, St. Louis, Missouri 63103, United States.
  • 9 Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037, United States.
PMID: 36988910 DOI: 10.1021/acschembio.2c00720
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.

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