Gene shifting: a novel therapy for mitochondrial myopathy.
Mutations in mitochondrial DNA (mtDNA) are the most frequent causes of mitochondrial myopathy in adults. In the majority of cases mutant and wild-type mtDNAs coexist, a condition referred to as mtDNA heteroplasmy; however, the relative frequency of each species varies widely in different cells and tissues. Nearly complete segregation of mutant and wild-type mtDNAs has been observed in the skeletal muscle of many patients. In such patients mutant mtDNAs pre-dominate in mature myofibers but are rare or undetectable in skeletal muscle satellite cells cultured in vitro. This pattern is thought to result from positive selection for the mutant mtDNA in post-mitotic myofibers and loss of the mutant by genetic drift in satellite cells. Satellite cells 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 or repair. We tested whether we could normalize the mtDNA genotype in mature myofibers in a patient with mitochondrial myopathy by enhancing the incorporation 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 activity and in muscle fiber cross-sectional area after a short period of concentric exercise training. These data show that it is possible to reverse the molecular events that led to expression of metabolic myopathy and demonstrate the effectiveness of this form of 'gene shifting' therapy.
Taivassalo
T
T
Montreal Neurological Institute, McGill University, Quebec, Canada.
Fu
K
K
Johns
T
T
Arnold
D
D
Karpati
G
G
Shoubridge
E A
EA
D003402:Creatine Kinase / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D005081:Exercise Therapy; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000628:therapy; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D012356:RNA, Transfer, Leu / Q000235:genetics
D004272:DNA, Mitochondrial; D012356:RNA, Transfer, Leu; D003402:Creatine Kinase