https://pubmed.ncbi.nlm.nih.gov/41421047/

Estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ) are orphan nuclear receptors that regulate genes involved in mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and the Krebs cycle. ERRs are essential for skeletal muscle adaptation to aerobic exercise and represent promising targets for exercise mimetic therapeutics. We previously developed an ERR pan-agonist, SLU-PP-332 (332), which improves aerobic performance in mice but lacks oral bioavailability. Here, we characterize SLU-PP-915 (915), a chemically distinct ERR pan-agonist that is orally bioavailable and exhibits potent in vivo exercise mimetic activity. Compound 915 enhances aerobic exercise performance (distance and duration) to a similar extent as 332 when administered intraperitoneally and maintains comparable efficacy when administered orally, adjusted for systemic exposure. Both compounds robustly induce the expression of DNA damage-inducible transcript 4 (Ddit4), a gene induced by acute aerobic exercise, with levels matching or exceeding levels induced by treadmill running, depending on the muscle examined. Notably, 915 synergizes with exercise training to further enhance Ddit4 and mitochondrial gene expression. These findings position orally active ERR agonists such as 915 as promising agents for the treatment of metabolic disorders (eg, obesity, type 2 diabetes, and metabolic disease-associated steatohepatitis), cardiovascular disease (heart failure), and muscle-related pathologies, including sarcopenia and muscular dystrophies. SLU-PP-915 offers a valuable chemical tool for exploring the chronic therapeutic potential of ERR activation. SIGNIFICANCE STATEMENT: The nuclear receptor estrogen receptor-related receptor plays an important role in driving the physiological adaptations to exercise. The article describes the ability of a pan-estrogen receptor-related receptor agonist SLU-PP-915, which also displays oral bioavailability, to enhance exercise capacity.