An orally active estrogen receptor-related receptor agonist, SLU-PP-915, enhances aerobic exercise capacity.
This preclinical study characterizes SLU-PP-915, a novel orally bioavailable pan-agonist of estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ) — orphan nuclear receptors that regulate mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and the Krebs cycle. The researchers compared SLU-PP-915 to a previously developed ERR pan-agonist, SLU-PP-332, which lacks oral bioavailability. In mouse models, both compounds similarly enhanced aerobic exercise performance (measured by running distance and duration) when administered intraperitoneally, and SLU-PP-915 maintained comparable efficacy via oral administration when adjusted for systemic exposure. Both compounds strongly induced expression of Ddit4, a gene upregulated by acute aerobic exercise, at levels matching or exceeding those produced by treadmill running, depending on the muscle group examined. Notably, SLU-PP-915 appeared to synergize with exercise training to further enhance Ddit4 and mitochondrial gene expression. The authors propose that orally active ERR agonists could have therapeutic relevance for metabolic disorders, cardiovascular disease, and muscle pathologies. Key limitations include exclusive use of animal models, with no human data reported, and the need for long-term safety and efficacy evaluation.
Why this grade: All experimental findings were generated exclusively in mouse models; no human trials or clinical data were included in this study.
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.
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