[Pharmacological Activation of ERRα/β/γ as an Exercise Mimetic: Potential Therapeutic Applications].
This systematic review examines the preclinical evidence for pharmacological activation of estrogen-related receptors (ERRα/β/γ) as a strategy to mimic the beneficial effects of exercise. The authors focused on synthetic pan-ERR agonists, particularly SLU-PP-332 and SLU-PP-915, reviewing experimental literature published between 2020 and 2024 from animal and cell-based models. The review found that these compounds appear to induce a gene expression program resembling that of acute aerobic exercise, dependent on ERRα, including activation of genes such as Ddit4 and Slc25a25. In preclinical obesity models, pan-ERR agonists were associated with enhanced fatty acid oxidation, increased oxidative-glycolytic (type IIa) muscle fiber composition, improved endurance capacity, reduced adiposity, better glycemic control, and increased basal energy expenditure, all without apparent toxicity signals. The compounds also showed potential to restore mitochondrial function and reduce inflammation in aging kidney models. The authors conclude that ERR activation is a promising exercise-mimetic strategy but explicitly acknowledge that no human clinical trials have been conducted, making translation to clinical practice premature. This represents a major limitation of the current evidence base.
Why this grade: Although framed as a systematic review, all included primary studies are animal or in vitro experiments; no human data are available, so the highest achievable evidence grade for the underlying claims remains animal-only.
Physical inactivity contributes to the development of chronic diseases. Activation of orphan nuclear receptors estrogen-related receptors (ERRα/β/γ) has emerged as a molecular strategy to mimic exercise-induced benefits. Aim To systematically review the current evidence on the physiological, molecular, and clinical effects of synthetic pan-ERR agonists, especially SLU-PP-332 and SLU-PP-915, in preclinical models and their potential as exercise mimetics. Methods A systematic review of scientific literature from 2020 to 2024 was conducted, including experimental studies in animals and cell models. Molecular mechanisms, effects on energy metabolism, muscle function, renal aging, and metabolic syndrome were analyzed. Results Pan-ERR agonists induce a gene expression program like acute aerobic exercise, dependent on ERRα, including activation of Ddit4 and Slc25a25. They enhance fatty acid oxidation, increase type IIa muscle fibers (oxidative-glycolytic, with mixed substrate utilization including fatty acids and glucose), and improve endurance. SLU-PP-332 and SLU-PP-915 reduce adiposity, improve glycemic control, and increase basal energy expenditure in obesity models, without evident toxicity. Additionally, they restore mitochondrial function and reduce inflammation in aging kidneys. Conclusions Pharmacological activation of ERRα/β/γ is a promising strategy as an exercise mimetic, with potential therapeutic applications in metabolic diseases, aging, and muscle-related conditions. Clinical trials are needed to confirm their efficacy and safety in humans.
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