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

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.

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function

“…Given that ERRα and ERRγ share many common target genes, 11 it is somewhat surprising that ERRγ is responsible for most of the 332-or 915-induced metabolic gene transcription. 21 Previous studies showed that all ERR isoforms exhibit a basal level of transcriptional activity independent of ligand binding. [109][110][111][112][113][114] ERR isoforms may have different levels of basal activity resulting in differentially inducible activity by ERR agonists.…”

“…In this study, we report the cardioprotective effect of a recently described pan-ERR agonist SLU-PP-332 (332) 21 and another structurally distinct pan-ERR agonist SLU-PP-915 (915) in pressure overload-induced HF. Our data show that 332/915, mainly through ERRγ, activated a broad spectrum of metabolic genes, enhanced fatty acid metabolism and mitochondrial function, and improved contractile function in transaortic constriction (TAC)-induced HF in vivo.…”

ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency

“…Collectively, our study demonstrates an essential role of the ERRα phosphorylation state in the control of muscle functions and energy metabolism during endurance exercise, highlighting ERRα hyperactivation as a potential therapeutic target to improve exercise performance and achieve long-term exercise benefits [ 73 ]. Future work will help delineate the exact contribution of post-translational mechanisms contributing to exercise-induced ERRα stabilization and overall activity.…”

Estrogen-Related Receptor α: A Key Transcription Factor in the Regulation of Energy Metabolism at an Organismic Level and a Target of the ABA/LANCL Hormone Receptor System

“…Dietary intake of γ-Oryzanol, a mixture of ferulic acid esters of terpenoids similar to ABA, used as a sports supplement, was shown to improve muscle strength and exercise endurance in mice by upregulating the transcription of both ERRα/γ via PPARδ [84]. In another study, a synthetic pan-ERR agonist was shown to induce a transcriptional reprogramming of type IIA muscle fibers as observed in aerobic training and to increase physical endurance in mice [85]. Finally, a recently published study describes how the expression of a mutated form of ERRα, resistant to phosphorylation-induced inactivation, induces muscle fiber aerobic transformation and increases mitochondrial biogenesis, metabolic fuel oxidation, and physical endurance in mice [86].…”