Zebrafish models for investigating skeletal muscle aging and sarcopenia

Sarcopenia is characterized by progressive loss of skeletal muscle strength, mass, and function during aging, driven by impaired proteostasis, mitochondrial dysfunction, altered metabolism, regenerative failure, and neuromuscular decline. Experimental models are needed to determine how these processes drive muscle degeneration and identify testable therapeutic mechanisms. Zebrafish combine whole-animal physiology with genetic manipulation, live imaging, and scalable phenotypic analysis, making them well suited to this purpose. Natural-aging, telomerase-deficient, dexamethasone-induced, high-fat-diet, and genetically defined zebrafish models each reproduce distinct structural, functional, metabolic, regenerative, or neuromuscular changes relevant to sarcopenia. In this Review, we compare study designs, measured endpoints, and mechanistic evidence to distinguish age-associated phenotypes from responses to induced stresses or defined molecular perturbations. Natural-aging models capture spontaneous age-associated changes in muscle structure, performance, and mitochondrial integrity; telomerase-deficient models reveal defects in tissue maintenance and regeneration; and dexamethasone- and high-fat-diet-induced models enable controlled analysis of proteostatic and metabolic stress. Genetic models directly test relationships between molecular perturbations and muscle phenotypes. Current studies, however, have notable limitations: swimming performance reflects whole-animal physiology rather than muscle strength, many markers do not directly measure pathway activity, and some models represent specific stress rather than primary sarcopenia. Across these models, shared phenotypes do not establish a common causal mechanism; model-specific findings require validation during natural aging and in mammalian and human studies.