Exercise Training Normalizes Mitochondrial Function in Myopathies Due to Heteroplasmic Mitochondrial DNA (mtDNA) Mutations (I4.010)

Objective: To assess effects of 6 months of exercise training in mitochondrial myopathy (MM). Background: Oxidative capacity (peak VO2) is low in MM due to low extraction of O2 from blood (low peak a-v O2 difference) while systemic O2 delivery (Q, cardiac output) and ventilation (VE) are high relative to VO2. The biochemical hallmark of MM in mtDNA mutations is deficiency of respiratory chain complexes (RCC) containing mtDNA-encoded subunits (e.g. complexes I, III, &/or IV). Design/Methods: Twenty-eight patients with heteroplamic mtDNA mutations (16 single large-scale deletions, 12 tRNA or coding region point mutations) and eleven age, gender-matched sedentary control subjects were evaluated at baseline and after 6 months of aerobic exercise training. Muscle biochemistry was assessed in needle quadriceps biopsies. Results: Training proportionally increased VO2 in controls (29.7±5.8 to 33.9±4.3 ml/kg/min) and patients (16.9 ± 4.9 to 18.7±5.1) and peak systemic a-vO2 diff (C=14.0±1.2 to 15.0±0.6; MM=9.7 ± 4.3 to 10.7±2.8). Peak cardiac output increased in controls (14.8±4.2 to 15.9±4.7 L/min), but was unchanged in patients; no significant change occurred in controls in Q relative to VO2 (5.6±0.7 to 5.2±0.4) or in VE/VO2 (44.9±9 to 43.0±11.1) but both of these measures normalized in MM (ΔQ/VO2, 9.1 ± 2.8 to 8.0±3.2; VE/VO2, 64.4 ± 15.2 to 59.0±15.5, p<.005). Training significantly increased muscle levels of citrate synthase, succinate dehydrogenase and complexes I, III, and IV in controls but only complexes I (3.4 ± 1.5 to 4.4±1.5), III (10.8 ± 6.5 to 12.7±6.0) and IV (3.3 ± 2.6 to 4.1±2.8) increased significantly in MM. Conclusions/Relevance: These results indicate that exercise training normalized mitochondrial function in MM due to heteroplasmic mtDNA mutations indicated by higer VO2 and lower ΔQ/ΔVO2 and peak VE/VO2 with selective increased activity of RCC containing mtDNA-encoded subunits consistent with enhanced function of wild-type mtDNA. Study supported by: NIAMS (R01AR50597 )