| Patients with mitochondrial myopathies characteristically exhibit pronounced exercise intolerance, often associated with lactic acidosis, tachycardia and muscle weakness. These clinical features are attributable to impaired electron transport chain function in skeletal muscle. The usual etiology is a primary defect in mitochondrial DNA (mtDNA), where the severity of impairment is presumably linked to the ratio of mutant to wild-type mtDNA. This dissertation presents novel therapeutic approaches to these genetic defects, aimed at attenuating mitochondrial dysfunction and ameliorating the clinical condition by employing exercise training alone or in conjunction with pharmacological therapy. Dichloroacetate (DCA) was administered to augment mitochondrial capacity by activating pyruvate dehydrogenase, thereby decreasing lactic acidosis. Endurance and resistance training paradigms were employed to induce mitochondrial and satellite cell proliferation respectively. The goals were to augment respiratory chain function, increase levels of wild type mtDNA, and reverse effects of chronic inactivity. The effects of these treatments on functional and mitochondrial capacity were defined by changes in: (1) work capacity, oxygen utilization, and circulatory responses during maximal exercise; (2) heart rate and blood lactate during submaximal exercise; (3) recovery kinetics of phosphate-containing metabolites measured using phosphorus magnetic resonance spectroscopy ( 31P MRS); (4) scores on a quality of life questionnaire. The cellular correlates for these indices were defined by changes in: (1) mitochondrial volume, (2) respiratory chain enzyme activity, and (3) levels of mutant/wild-type mtDNA. Although DCA administration alone lowered blood lactate, endurance training was more effective in improving exercise capacity, heart rate and blood lactate, 31P MRS recovery kinetics, and quality of life. Increased mitochondrial volume and respiratory chain function were closely linked to these improvements and occurred despite increases in mutant/wild-type mtDNA, suggesting that absolute numbers of wild-type mtDNA, rather than the ratio alone, is functionally important. The variability of the training effect and long-term consequences of increased mutant/wild-type mtDNA raises concern about endurance training as a general treatment option. In contrast, resistance training led to remarkable decreases in mutant/wild-type mtDNA in a preliminary study in a patient with mitochondrial myopathy. This suggests that "gene shifting" may hold promise for improving muscle function and quality of life in many patients with mitochondrial myopathies. |
