Gene shifting: a novel therapy for mitochondrial myopathy

Mutations in mitochondrial DNA (mtDNA) are the most frequent causes of mito chondrial myopathy in adults, In the majority of cases mutant and wild-type mtDNAs coexist, a condition referred to as mtDNA heteroplasmy; however, th e relative frequency of each species varies widely in different cells and t issues. Nearly complete segregation of mutant and wild-type mtDNAs has been observed in the skeletal muscle of many patients, In such patients mutant mtDNAs predominate in mature myofibers but are rare or undetectable in skel etal muscle satellite cells cultured in vitro, This pattern is thought to r esult from positive selection for the mutant mtDNA in post-mitotic myofiber s and loss of the mutant by genetic drift in satellite cells, Satellite cel ls are dormant myoblasts that can be stimulated to re-enter the cell cycle and fuse with existing myofibers in response to signals for muscle growth o r repair. We tested whether we could normalize the mtDNA genotype in mature myofibers in a patient with mitochondrial myopathy by enhancing the incorp oration of satellite cells through regeneration following injury or muscle hypertrophy, induced by either eccentric or concentric resistance exercise training. We show a remarkable increase in the ratio of wild-type to mutant mtDNAs, in the proportion of muscle fibers with normal respiratory chain a ctivity and in muscle fiber cross-sectional area after a short period of co ncentric exercise training, These data show that it is possible to reverse the molecular events that led to expression of metabolic myopathy and demon strate the effectiveness of this form of 'gene shifting' therapy.