Defects in the mitochondrial ATP generating system are one of the most commonly inherited neurological disorders, but remain without treatment. We have recently shown that modulation of the PGC-1 level in skeletal muscle of a mitochondrial myopathy mouse model offers a therapeutic approach. Here we analyzed if endurance exercise, which is known to be associated with an increased PGC-1 level in muscle, offers the same beneficial effect. We subjected male and female mice, which develop a severe mitochondrial myopathy due to a cytochrome c oxidase deficiency at 3 months of age, to endurance exercise training and monitored phenotypical and metabolical changes. Sedentary myopathy and wild-type mice were used as controls. Exercise increased PGC-1 in muscle resulting in increased mitochondrial biogenesis and successfully stimulated residual respiratory capacity in muscle tissue. As a consequence, ATP levels were increased in exercised mice compared to sedentary myopathy animals, which resulted in a delayed onset of the myopathy and a prolonged life span of the exercised mice. As an added benefit, endurance exercise induced anti-oxidant enzymes. The overall protective effect of endurance exercise delayed the onset of the mitochondrial myopathy and increased life-expectancy in the mouse model. Thus, stimulating residual OXPHOS function in the affected muscle by inducing mitochondrial biogenesis through endurance exercise might offer a valuable therapeutic intervention for mitochondrial myopathy patients.