Comparative analysis of muscle pathologies and metabolic signaling in mouse models of mitochondrial dysfunction

mice, a premature aging model, and Mito-mice∆, a mitochondrial disease model. Both exhibited abnormal histochemical activity in mitochondrial respiration complex II and IV, yet differed in severity of mitochondrial accumulation and fiber-type-specific vulnerability. To explore the basis of these differences, we examined metabolic signaling pathways. Notably, phosphorylation levels of AMPK, a key sensor activated in response to altered AMP/ATP ratios, were significantly different between the two models. These findings suggest that muscle pathology induced by mitochondrial dysfunction is determined less by the extent of abnormalities in mitochondrial respiration complexes than by the specific metabolic signaling pathways engaged. This highlights the importance of signaling context in shaping disease mechanisms and underscores the need to consider pathway-specific responses when investigating mitochondrial dysfunction in skeletal muscle.