Oxidative capacity correlates with muscle mutation load in mitochondrial myopathy

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Abstract
The purpose of this study was to investigate the correlation between the level of mutated mitochondrial DNA in muscle and oxidative capacity in 24 patients with mitochondrial myopathy (MM). Maximal oxygen uptake (VO2max), workload (Wmax), and venous plasma lactate levels were measured during an incremental cycle test to exhaustion in 17 patients with point mutations of mtDNA and in seven with single, large‐scale deletions of mtDNA (chronic progressive external ophthalmoplegia [CPEO]). Results were compared with those in 25 healthy matched subjects. The mutation load in MM patients was 67 ± 5% (range, 29 – 99%). VO2max and Wmax correlated with percentage of heteroplasmy (r > 0.82; p < 0.005) and were lower in patients versus healthy subjects (p < 0.000005). Exercise‐induced peak increases in heart rate, ventilation, and resting plasma lactate levels correlated with muscle mutation load (r > 0.71; p < 0.005). Exercise‐induced increases in plasma lactate correlated with muscle mutation load in CPEO patients (r = 0.95; p < 0.005). Impaired oxidative capacity and ragged red muscle fibers were found in CPEO and 3243A→G patients with mutation loads as low as 45 and 57%, respectively. The study indicates that oxidative capacity correlates directly with skeletal muscle mutation load in MM patients, and that the mutation threshold level for impaired oxidative metabolism in MM patients is lower than found in in vitro studies. Ann Neurol 2003