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Synergist ablation (SA) is a well-established model of mechanical overload-induced hypertrophy in rodents, commonly used to infer skeletal muscle adaptation to resistance training in humans. Given the critical role of skeletal muscle atrophy in chronic conditions such as neuromuscular, metabolic, and cardiopulmonary disorders, SA represents a promising preclinical tool to study muscle hypertrophy mechanisms in pathological states. However, while extensively characterized in healthy animals, the potential applications of SA in disease models remain largely overlooked. This Mini-Review summarizes existing studies employing SA in rodent disease models, highlighting the diverse hypertrophic responses observed across conditions, including Duchenne muscular dystrophy, obesity, diabetes, cancer cachexia, and chronic kidney disease. Although hypertrophy gains are generally attenuated in diseased animals compared to healthy controls, SA-induced overload provides valuable insights into disease-specific regulatory mechanisms, including alterations in intracellular signaling, fiber-type transitions, and disease phenotype. We also discuss the strengths and limitations of SA as a preclinical model for resistance training in disease contexts and propose its broader adoption for mechanistic investigations into skeletal muscle plasticity under pathological conditions.