Exercise training induces muscle remodeling independent of estrogen-related receptor (ERR) expression in adult...

Locomotor capacity is a major determinant of fitness and is strongly modulated by exercise-induced physiological plasticity. In vertebrates, sustained submaximal exercise typically promotes a shift toward an aerobic muscle phenotype, characterized by enhanced oxidative capacity, angiogenesis and contractile remodeling. In mammals, these plastic responses are largely mediated by estrogen-related receptors (ERRs) and their coregulators; however, whether these regulatory mechanisms are conserved in fish remains unclear. Here, we tested the role of ERRs in exercise acclimation in adult zebrafish (Danio rerio), a laboratory model with multiple ERR paralogs following teleost-specific genome duplication events. Following 6 weeks of moderate intensity forced-swimming training, we assessed whole-animal performance (critical swimming speed) and metabolism alongside skeletal muscle contractile and metabolic phenotypes. We applied proteomic profiling and pathway enrichment analyses to evaluate changes in ERR expression and activity, and to identify molecular networks associated with muscle remodeling. Exercise training improved locomotor performance by increasing critical swimming speed and induced skeletal muscle remodeling consistent with a more oxidative and vascularized phenotype, without detectable changes in resting or maximal metabolic rates. Additionally, improvements in exercise training capacity were not accompanied by detectable changes in ERR expression as determined by proteomic analyses. Instead, it suggested alternative regulation distinct from canonical mammalian ERR signaling pathways. Our results demonstrate that zebrafish exhibit conserved exercise-induced phenotypic outcomes but rely on fundamentally different molecular mechanisms than mammals. These findings highlight the value and limitations of zebrafish as models for exercise physiology and underscore the evolutionary flexibility of signaling pathways governing conserved functional phenotypes.