Ketogenic diet induces metabolic remodeling and alters myogenic markers in skeletal muscle of obese male mice subjected to medial meniscus destabilization

Osteoarthritis (OA) is strongly associated with obesity, and weight reduction is recommended to reduce joint loading and improve symptoms. However, the effects of ketogenic diet (KD)-induced weight loss on skeletal muscle under combined metabolic and biomechanical stress remain poorly understood. We investigated skeletal muscle adaptation to KD in a mouse model that combined obesity with knee joint injury. Male C57BL/6J mice were rendered obese by high-fat diet feeding and subjected to destabilization of the medial meniscus. Following surgery, animals remained on high-fat diet (HFD) or were switched to chow diet (CD) or KD for 8 weeks. Gastrocnemius muscle was analysed at the molecular level, and serum underwent targeted metabolomic profiling. KD induced weight loss, reduced glycemia and increased circulating β-hydroxybutyrate without decreasing absolute gastrocnemius mass or causing sustained deterioration in motor performance. In skeletal muscle, KD increased Acat1 expression and induced a transcriptional profile consistent with enhanced capacity for lipid-derived substrate utilization, including increased Ppargc1a, Acadl, Cpt1b and Pdk4 expression. These changes were accompanied by selective remodelling of circulating acylcarnitines, particularly long-chain and hydroxyacylcarnitine species, indicating altered systemic. KD also increased expression of the myogenic-associated markers Pax7, Myf5 and MyoD1 hinting at a possible alteration in satellite cell state and pathways connected to myogenesis. Overall, KD promoted selective systemic and skeletal muscle metabolic remodelling in, characterized by altered lipid-derived substrate handling, activation of an oxidative transcriptional program and transcriptional modulation of myogenic-associated markers without sustained deterioration in motor performance during weight loss.