<p>Mitochondria are vital organelles that produce ATP through oxidative phosphorylation, sustaining skeletal muscle, a tissue with high energy demand. When mitochondrial function is impaired, intracellular energy and nutrient balance are disrupted, activating metabolic signaling pathways. However, these responses vary across models, and the relationship between muscle pathology and signaling remains unclear. To address this, we compared soleus muscle pathology in <i>Polg</i>^mut/mut 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.</p>