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

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

Publication Date

4-21-2023

Journal

ACS Chemical Biology

DOI

10.1021/acschembio.2c00720

PMID

36988910

PMCID

PMC11584170

PubMedCentral® Posted Date

11-22-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Mice, Exercise Tolerance, Muscle Fibers, Skeletal, Muscle, Skeletal, Receptors, Estrogen, Estrogens, ERRalpha Estrogen-Related Receptor

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.