Exercise Testing, Physical Training and Fatigue in Patients with Mitochondrial Myopathy Related to mtDNA Mutations.

Mutations in mitochondrial DNA (mtDNA) cause disruption of the oxidative phosphorylation chain and impair energy production in cells throughout the human body. Primary mitochondrial disorders due to mtDNA mutations can present with symptoms from adult-onset mono-organ affection to death in infancy due to multi-organ involvement. The heterogeneous phenotypes that patients with a mutation of mtDNA can present with are thought, at least to some extent, to be a result of differences in mtDNA mutation load among patients and even among tissues in the individual. The most common symptom in patients with mitochondrial myopathy (MM) is exercise intolerance. Since mitochondrial function can be assessed directly in skeletal muscle, exercise studies can be used to elucidate the physiological consequences of defective mitochondria due to mtDNA mutations. Moreover, exercise tests have been developed for diagnostic purposes for mitochondrial myopathy. In this review, we present the rationale for exercise testing of patients with MM due to mutations in mtDNA, evaluate the diagnostic yield of exercise tests for MM and touch upon how exercise tests can be used as tools for follow-up to assess disease course or effects of treatment interventions.

Mutation Load of Single, Large-Scale Deletions of mtDNA in Mitotic and Postmitotic Tissues.

It is generally accepted that patients with chronic progressive ophthalmoplegia caused by single large-scale deletion (SLD) of mitochondrial DNA (mtDNA) only harbor mutation in skeletal and eye muscles. The aim of this study was to investigate the presence and the level of heteroplasmy of mtDNA deletions in mitotic tissues of patients displaying mtDNA deletion of mitotic tissues in patients with SLDs and pure muscle phenotype. MtDNA mutation load was studied in three mitotic (urine epithelial cells, buccal mucosa, and blood) and one postmitotic (skeletal muscle) tissues in 17 patients with SLDs of mtDNA and pure muscle involvement. All patients had mtDNA deletion in skeletal muscle, and 78% of the patients also displayed the mtDNA deletion in mitotic tissues. The mtDNA mutation load was higher in skeletal muscle versus mitotic tissues. The mtDNA mutation load did not correlate with age of sampling of tissues, but there was a correlation between the mtDNA mutations load in skeletal muscle and (1) the site of 5' end breaking point of the SLD, (2) the size of SLD, (3) the number of affected tRNAs, and (4) age at onset (r > 0.58, P < 0.05). The findings indicate that mtDNA mutation in mitotic tissue is common in patients with SLDs of mtDNA. The lack of correlation between age of tissue sampling, age at onset, and mtDNA mutation load in mitotic tissues indicates that there is no extensive post-natal modification of mtDNA mutation load in mitotic tissues of patients with pure muscle phenotype.

Effect of Aerobic Exercise Training and Deconditioning on Oxidative Capacity and Muscle Mitochondrial Enzyme Machinery in Young and Elderly Individuals.

Mitochondrial dysfunction is thought to be involved in age-related loss of muscle mass and function (sarcopenia). Since the degree of physical activity is vital for skeletal muscle mitochondrial function and content, the aim of this study was to investigate the effect of 6 weeks of aerobic exercise training and 8 weeks of deconditioning on functional parameters of aerobic capacity and markers of muscle mitochondrial function in elderly compared to young individuals. In 11 healthy, elderly (80 ± 4 years old) and 10 healthy, young (24 ± 3 years old) volunteers, aerobic training improved maximal oxygen consumption rate by 13%, maximal workload by 34%, endurance capacity by 2.4-fold and exercise economy by 12% in the elderly to the same extent as in young individuals. This evidence was accompanied by a similar training-induced increase in muscle citrate synthase (CS) (31%) and mitochondrial complex I-IV activities (51-163%) in elderly and young individuals. After 8 weeks of deconditioning, endurance capacity (-20%), and enzyme activity of CS (-18%) and complex I (-40%), III (-25%), and IV (-26%) decreased in the elderly to a larger extent than in young individuals. In conclusion, we found that elderly have a physiological normal ability to improve aerobic capacity and mitochondrial function with aerobic training compared to young individuals, but had a faster decline in endurance performance and muscle mitochondrial enzyme activity after deconditioning, suggesting an age-related issue in maintaining oxidative metabolism.

Preserved Capacity for Adaptations in Strength and Muscle Regulatory Factors in Elderly in Response to Resistance Exercise Training and Deconditioning.

Aging is related to an inevitable loss of muscle mass and strength. The mechanisms behind age-related loss of muscle tissue are not fully understood but may, among other things, be induced by age-related differences in myogenic regulatory factors. Resistance exercise training and deconditioning offers a model to investigate differences in myogenic regulatory factors that may be important for age-related loss of muscle mass and strength. Nine elderly (82 ± 7 years old) and nine young, healthy persons (22 ± 2 years old) participated in the study. Exercise consisted of six weeks of resistance training of the quadriceps muscle followed by eight weeks of deconditioning. Muscle biopsy samples before and after training and during the deconditioning period were analyzed for MyoD, myogenin, insulin-like growth-factor I receptor, activin receptor IIB, smad2, porin, and citrate synthase. Muscle strength improved with resistance training by 78% (95.0 ± 22.0 kg) in the elderly to a similar extent as in the young participants (83.5%; 178.2 ± 44.2 kg) and returned to baseline in both groups after eight weeks of deconditioning. No difference was seen in expression of muscle regulatory factors between elderly and young in response to exercise training and deconditioning. In conclusion, the capacity to gain muscle strength with resistance exercise training in elderly was not impaired, highlighting this as a potent tool to combat age-related loss of muscle function, possibly due to preserved regulation of myogenic factors in elderly compared with young muscle.

Quantitative electromyography: Normative data in paraspinal muscles.

BACKGROUND: Quantitative electromyography of paraspinal muscle is a valuable diagnostic tool, but normative data are lacking. METHODS: Needle electromyography (EMG) was obtained in 65 healthy subjects (49% men, 51% women) aged 21 to 82 years at C7, Th10, and L5 segments bilaterally. The incidence of spontaneous activity; motor unit potential (MUP) amplitudes, durations, and the incidence of polyphasic potentials; and the recruitment pattern at maximal voluntary contraction (MVC) were evaluated. RESULTS: The incidence of fibrillation potentials was similar to limb muscles. The mean MUP duration and amplitude, and the amplitude at MVC increased caudally, while the incidence of polyphasic potentials was similar at all levels. EMG parameters did not correlate with sex or age. CONCLUSIONS: In contrast to limb muscles, EMG parameters did not change with age, while polyphasic potentials were more frequent in paraspinal muscle than in limb muscles. The EMG gradient suggests larger motor units at more caudal segments.

Palbociclib in combination with simvastatin induce severe rhabdomyolysis: a case report.

BACKGROUND: Palbociclib is a selective well-tolerated antineoplastic drug used in the treatment of advanced HER2-negative, estrogen-receptor positive breast cancer that has shown significant improvement in progression-free survival. We present a patient that developed severe rhabdomyolysis with tetra-affection and loss of gait after initiating the first cycle of Palbociclib concomitantly with Simvastatin 40 mg treatment. CASE PRESENTATION: A 71-year-old woman with metastatic breast cancer developed tetraparesis and near fatal rhabdomyolysis after initiation of first cycle Palbociclib. For 10 years prior to this treatment, the patient had been treated with Simvastatin without myalgia or other neuromuscular complaints prior to the first cycle of Palbociclib. The patient was admitted at the neurology department, where Palbociclib and Simvastatin were discontinued. The patient was aggressively hydrated and treated with intravenous immunoglobulin therapy with slowly remission and finally regaining independent gait function. Evaluation showed a negative myositis antibody work-up. Muscle magnetic resonance imaging showed edema in multiple foci, but skeletal muscle biopsy did not show necrosis. Post discharge genetic analysis showed single heterozygosity for nucleotide polymorphism rs4149056. CONCLUSION: We present a patient who developed severe rhabdomyolysis induced by a combination of Palbociclib and Simvastatin treatment. Rhabdomyolysis was most likely induced by toxic plasma concentrations of Simvastatin due to Palbociclibs inhibition of the CYP3A4 enzyme in combination with a decreased hepatic uptake of Simvastatin due to single nucleotide polymorphism rs4149056. The study underscores that combining Simvastatin and Palbociclib should be done cautiously and genetic testing of the rs4149056 SNP is warranted. If present, Simvastatin should be discontinued or replaced with a lesser myopathic statin in regard to patients risk of cardiovascular events.

Adaptations in Mitochondrial Enzymatic Activity Occurs Independent of Genomic Dosage in Response to Aerobic Exercise Training and Deconditioning in Human Skeletal Muscle.

Mitochondrial DNA (mtDNA) replication is thought to be an integral part of exercise-training-induced mitochondrial adaptations. Thus, mtDNA level is often used as an index of mitochondrial adaptations in training studies. We investigated the hypothesis that endurance exercise training-induced mitochondrial enzymatic changes are independent of genomic dosage by studying mtDNA content in skeletal muscle in response to six weeks of knee-extensor exercise training followed by four weeks of deconditioning in one leg, comparing results to the contralateral untrained leg, in 10 healthy, untrained male volunteers. Findings were compared to citrate synthase activity, mitochondrial complex activities, and content of mitochondrial membrane markers (porin and cardiolipin). One-legged knee-extensor exercise increased endurance performance by 120%, which was accompanied by increases in power output and peak oxygen uptake of 49% and 33%, respectively (p < 0.01). Citrate synthase and mitochondrial respiratory chain complex I⁻IV activities were increased by 51% and 46⁻61%, respectively, in the trained leg (p < 0.001). Despite a substantial training-induced increase in mitochondrial activity of TCA and ETC enzymes, there was no change in mtDNA and mitochondrial inner and outer membrane markers (i.e. cardiolipin and porin). Conversely, deconditioning reduced endurance capacity by 41%, muscle citrate synthase activity by 32%, and mitochondrial complex I⁻IV activities by 29⁻36% (p < 0.05), without any change in mtDNA and porin and cardiolipin content in the previously trained leg. The findings demonstrate that the adaptations in mitochondrial enzymatic activity after aerobic endurance exercise training and the opposite effects of deconditioning are independent of changes in the number of mitochondrial genomes, and likely relate to changes in the rate of transcription of mtDNA.

Protein-carbohydrate supplements improve muscle protein balance in muscular dystrophy patients after endurance exercise: a placebo-controlled crossover study.

In healthy individuals, postexercise protein supplementation increases muscle protein anabolism. In patients with muscular dystrophies, aerobic exercise improves muscle function, but the effect of exercise on muscle protein balance is unknown. Therefore, we investigated 1) muscle protein balance before, during, and after exercise and 2) the effect of postexercise protein-carbohydrate supplementation on muscle protein balance in patients with muscular dystrophies. In 17 patients [7 women and 10 men, aged 33 ± 11 yr (18-52), body mass index: 22 ± 3 kg/m(2) (16-26)] and 8 healthy matched controls [3 women and 5 men, age 33 ± 13 years (19-54), body mass index: 23 ± 3 kg/m(2) (19-27)], muscle protein synthesis, breakdown, and fractional synthesis rates (FSR) were measured across the leg using tracer dilution methodology on two occasions, with and without oral postexercise protein-carbohydrate supplementation. In patients, muscle protein breakdown increased in the recovery period (11 ± 1 µmol phenylalanine/min) vs. rest (8 ± 1 µmol phenylalanine/min, P = 0.02), enhancing net muscle protein loss. In contrast, postexercise protein-carbohydrate supplementation reduced protein breakdown, abolished net muscle protein loss, and increased the muscle FSR in patients (0.04 to 0.06%/h; P = 0.03). In conclusion, postexercise protein-carbohydrate supplementation reduces skeletal mixed-muscle protein breakdown, enhances FSR, resulting in a reduced net muscle loss in patients with muscular dystrophies. The findings suggest that postexercise protein-carbohydrate supplementation could be an important add-on to exercise training therapy in muscular dystrophies, and long-term studies of postexercise protein-carbohydrate supplementation are warranted in these conditions.

Lactate metabolism during exercise in patients with mitochondrial myopathy.

Patients with mitochondrial DNA mutations often have elevated plasma lactate at rest and during exercise, but it is unknown whether the high lactate levels are caused by a high production, an impaired oxidation or a combination. We studied lactate kinetics in 10 patients with mtDNA mutations and 10 matched healthy control subjects at rest and during cycle exercise with a combination of femoral arterio-venous differences of lactate, and lactate tracer dilution methodology. During exercise, lactate concentration and production rates were several-fold higher in patients, but despite mitochondrial dysfunction, lactate was oxidized in muscle to the same extent as in healthy control subjects. This surprisingly high ability to burn lactate in working muscle with defective mitochondria, probably relates to the variability of oxidative capacity among muscle fibers. The data suggests that lactate is not solely an indicator of impaired oxidative capacity, but an important fuel for oxidative metabolism, even in muscle with severely impaired mitochondrial function.

Muscle phenotype in patients with myotonic dystrophy type 1.

INTRODUCTION: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. METHODS: In 38 patients, muscle strength was tested by hand-held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na(+)-K(+) pump content. RESULTS: Muscle strength correlated with a decline in Na(+)-K(+) pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na(+)-K(+) pump content. Histopathologically, we found few centrally placed nuclei (range 0.2-6.9%). CONCLUSIONS: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1.

Influence of erythrocyte oxygenation and intravascular ATP on resting and exercising skeletal muscle blood flow in humans with mitochondrial myopathy.

Oxygen (O2) extraction is impaired in exercising skeletal muscle of humans with mutations of mitochondrial DNA (mtDNA), but the muscle hemodynamic response to exercise has never been directly investigated. This study sought to examine the extent to which human skeletal muscle perfusion can increase without reductions in blood oxygenation and to determine whether erythrocyte O2 off-loading and related ATP vascular mechanisms are impaired in humans with mutations of mtDNA. Leg vascular hemodynamic, oxygenation and ATP were investigated in ten patients with mtDNA mutations and ten matched healthy control subjects: 1) at rest during normoxia, hypoxia, hyperoxia and intra-femoral artery ATP infusion, and 2) during passive and dynamic one-legged knee-extensor exercises. At rest, blood flow (LBF), femoral arterial and venous blood oxygenation and plasma ATP were similar in the two groups. During dynamic exercise, LBF and vascular conductance increased 9-10 fold in the patients despite erythrocyte oxygenation and leg O2 extraction remained unchanged (p<0.01). In the patients, workload-adjusted LBF was 28% to 62% higher during submaximal- and maximal exercises and was associated with augmented plasma ATP. The appropriate hemodynamic adjustments during severe hypoxia and ATP infusion suggest that erythrocyte O2 off-loading and related ATP vascular mechanisms are intact in patients with mtDNA mutations. Furthermore, greater increase in plasma ATP and LBF at a given metabolic demand in the patients, in concert with unchanged oxyhemoglobin, suggest that erythrocyte O2 off-loading is not obligatory for the exercise-induced increase in blood flow and intravascular ATP concentration.

Limited diagnostic value of enzyme analysis in patients with mitochondrial tRNA mutations.

We evaluated the diagnostic value of respiratory chain (RC) enzyme analysis of muscle in adult patients with mitochondrial myopathy (MM). RC enzyme activity was measured in muscle biopsies from 39 patients who carry either the 3243A>G mutation, other tRNA point mutations, or single, large-scale deletions of mtDNA. Findings were compared with those obtained from asymptomatic relatives with the 3243A>G mutation, myotonic dystrophy patients, and healthy subjects. Plasma lactate concentration, maximal oxygen uptake, and ragged-red fibers/cytochrome c-negative fibers in muscle were also determined. Only 10% of patients with the 3243A>G point mutation had decreased enzyme activity of one or more RC complexes, whereas this was the case for 83% of patients with other point mutations and 62% of patients with deletions. Abnormal muscle histochemistry was found in 65%, 100%, and 85% of patients, respectively, in these three groups. The results indicate that RC enzyme analysis in muscle is not a sensitive test for MM in adults. In these patients, abnormal muscle histochemistry appears to be a better predictor ofMM.

Effect of changes in fat availability on exercise capacity in McArdle disease.

BACKGROUND: The major fuel for exercising muscle at low exercise intensities is fat. OBJECTIVE: To investigate the role of fat metabolism in McArdle disease (also known as glycogen storage disease type V), an inborn error of muscle glycogenolysis, by manipulating free fatty acid availability for oxidation during exercise. DESIGN: Randomized, placebo-controlled, crossover trial. SETTING: Hospitalized care. PATIENTS: Ten patients (8 men and 2 women) with McArdle disease. INTERVENTIONS: Patients cycled at a constant workload corresponding to 70% of their maximum oxygen consumption. In random order and on separate days, patients received nicotinic acid (a known blocker of lipolysis) to decrease the availability of free fatty acids or 20% Intralipid infusion to increase free fatty acid availability during exercise. Results were compared with placebo (isotonic sodium chloride solution infusion) and glucose infusion trials. MAIN OUTCOME MEASURES: Exercise tolerance was assessed by heart rate response to exercise during different infusions. RESULTS: Free fatty acid levels more than tripled by Intralipid infusion and were halved by nicotinic acid administration. Heart rate was significantly higher during exercise in the Intralipid infusion and nicotinic acid trials compared with the placebo and glucose infusion trials, an effect that was observed before and after the patients had experienced the second wind phenomenon. CONCLUSIONS: Lipids are an important source of fuel for exercising muscle in McArdle disease, but maximal rates of fat oxidation seem limited and cannot be increased above physiologically normal rates during exercise. This limitation is probably caused by a metabolic bottleneck in the tricarboxylic acid cycle due to impaired glycolytic flux in McArdle disease. Therapies aimed at enhancing fat use in McArdle disease should be combined with interventions targeting expansion of the tricarboxylic acid cycle.

Endurance training improves fitness and strength in patients with Becker muscular dystrophy.

Studies in a dystrophinopathy model (the mdx mouse) suggest that exercise training may be deleterious for muscle integrity, but exercise has never been studied in detail in humans with defects of dystrophin. We studied the effect of endurance training on conditioning in patients with the dystrophinopathy, Becker muscular dystrophy (BMD). Eleven patients with BMD and seven matched, healthy subjects cycled 50, 30 min sessions at 65% of their maximal oxygen uptake (VO(2max)) over 12 weeks, and six patients continued cycling for 1 year. VO(2max), muscle biopsies, echocardiography, plasma creatine kinase (CK), lower extremity muscle strength and self-reported questionnaires were evaluated before, after 12 weeks and 1 year of training. Endurance training for 12 weeks, improved VO(2max) by 47 +/- 11% and maximal workload by 80 +/- 19% in patients (P < 0.005). This was significantly higher than in healthy subjects (16 +/- 2% and 17 +/- 2%). CK levels did not increase with training, and number of central nuclei, necrotic fibres and fibres expressing neonatal myosin heavy chain did not change in muscle biopsies. Strength in muscles involved in cycle exercise (knee extension, and dorsi- and plantar-flexion) increased significantly by 13-40%. Cardiac pump function, measured by echocardiography, did not change with training. All improvements and safety markers were maintained after 1 year of training. Endurance training is a safe method to increase exercise performance and daily function in patients with BMD. The findings support an active approach to rehabilitation of patients with BMD.

Phenotype and clinical course in a family with a new de novo Twinkle gene mutation.

The Twinkle gene product is important for mtDNA replication. Only a few reports have investigated the clinically effect of mutations in this gene. We describe a new de novo mutation (1110C>A) in the PEO1 gene in a mother and her two sons. The mother had progressive ophthalmoplegia, limb weakness, sensory neuropathy, elevated resting plasma lactate, glucose intolerance and impaired VO2max while her sons only had mild ptosis. In accordance with the clinical presentation, abnormal morphological findings in muscle and multiple deletions and depletion of mtDNA in muscle were more pronounced in the proband than in her sons.

Haemodynamic responses to exercise, ATP infusion and thigh compression in humans: insight into the role of muscle mechanisms on cardiovascular function.

The muscle pump and muscle vasodilatory mechanism are thought to play important roles in increasing and maintaining muscle perfusion and cardiac output ((.)Q) during exercise, but their actual contributions remain uncertain. To evaluate the role of the skeletal muscle pump and vasodilatation on cardiovascular function during exercise, we determined leg and systemic haemodynamic responses in healthy men during (1) incremental one-legged knee-extensor exercise, (2) step-wise femoral artery ATP infusion at rest, (3) passive exercise (n=10), (4)femoral vein or artery ATP infusion (n=6), and (5) cyclic thigh compressions at rest and during passive and voluntary exercise (n=7). Incremental exercise resulted in progressive increases in leg blood flow (DeltaLBF 7.4 +/- 0.7 l min(-1)), cardiac output (Delta (.)Q 8.7 +/- 0.7 l min(-1)), mean arterial pressure (DeltaMAP 51 +/- 5 mmHg), and leg and systemic oxygen delivery and (.)VO2 . Arterial ATP infusion resulted in similar increases in (.)Q , LBF, and systemic and leg oxygen delivery, but central venous pressure and muscle metabolism remained unchanged and MAP was reduced. In contrast,femoral vein ATP infusion did not alter LBF, (.)Q or MAP. Passive exercise also increased blood flow (DeltaLBF 0.7 +/- 0.1 l min(-1)), yet the increase in muscle and systemic perfusion, unrelated to elevations in aerobic metabolism, accounted only for approximately 5% of peak exercise hyperaemia.Likewise, thigh compressions alone or in combination with passive exercise increased blood flow (DeltaLBF 0.5-0.7 l min(-1)) without altering (.)Q, MAP or (.)VO2. These findings suggest that the skeletal muscle pump is not obligatory for sustaining venous return, central venous pressure,stroke volume and (.)Q or maintaining muscle blood flow during one-legged exercise in humans.Further, its contribution to muscle and systemic peak exercise hyperaemia appears to be minimal in comparison to the effects of muscle vasodilatation.

Muscle phenotype and mutation load in 51 persons with the 3243A>G mitochondrial DNA mutation.

BACKGROUND: Mitochondrial disorders are generally not associated with a clear phenotype-genotype relationship, which complicates the understanding of the disease and genetic counseling. OBJECTIVE: To investigate the relationship between the muscle and blood mitochondrial DNA mutation load and phenotype. DESIGN: Survey. SETTING: The Neuromuscular Research Unit, Rigshospitalet, Copenhagen, Denmark. PARTICIPANTS: Fifty-one persons with the 3243A>G point mutation of mitochondrial DNA, and 20 healthy control subjects. METHODS: We recorded the maximal oxygen uptake (Vo(2)max), maximal workload, resting and peak-exercise plasma lactate levels, muscle and blood mutation load, muscle morphology, and presence of diabetes mellitus and hearing impairment in all subjects. RESULTS: Muscle mutation load (mean +/- SE, 50% +/- 5%; range, 2%-95%) correlated with Vo(2)max and resting plasma lactate level (P<.001; R>/=0.64). All persons except 5 with a muscle mutation load above 50% had abnormal Vo(2)max and morphology on muscle biopsy findings. Persons with hearing impairment and diabetes mellitus had a muscle mutation load above 65%. The mutation load in blood (mean +/- SE, 18% +/- 3%; range, 0%-61%) did not correlate with Vo(2)max, resting plasma lactate levels, or presence of hearing impairment or diabetes mellitus. CONCLUSIONS: This study demonstrates a close relationship between the muscle mutation load and phenotype in persons carrying the 3243A>G mutation. The lack of correlation between the mutation load in blood and symptoms from other tissues emphasizes the importance of assessing phenotype-genotype correlations in the same tissue in mitochondrial disease. The results indicate that the threshold of muscle mutation load at which oxidative impairment occurs can be as low as 50%, which is as much as 40% lower than that suggested by in vitro studies.

Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy.

Exercise intolerance is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still unsettled whether exercise training is safe and beneficial for patients with MM. To address this, we studied the effect of 12 weeks cycle training on exercise capacity, quality of life and underlying molecular and cellular events in five patients with single large-scale deletions, one with a microdeletion and 14 with point mutations of mitochondrial DNA (mtDNA), and 13 healthy subjects. Each training session lasted 30 min, and was performed at an intensity of 70% of VO2max (maximal oxygen uptake). Each subject performed 50 training sessions in 12 weeks. All subjects were evaluated before and after training, and 13 MM patients were studied after 8 weeks of deconditioning. Evaluation included VO2max and mutation load and mtDNA quantity, mitochondrial enzymatic activity, and number of centrally nucleated, apoptotic, ragged red and cytochrome oxidase (COX)-negative fibres in muscle biopsies from the quadriceps muscle. After 12 weeks of training, VO2max and muscle citrate synthase increased in MM (26 and 67%) and healthy (17 and 65%) subjects, while mtDNA quantity in muscle only increased in the MM patients (81%). In the MM patients, training did not change mtDNA mutation load in muscle, mitochondrial enzyme complex activities, muscle morphology and plasma creatine kinase. After deconditioning, VO2max and citrate synthase activity returned to values before training, while muscle mtDNA mutation load decreased. These findings show that aerobic training efficiently improves oxidative capacity in MM patients. Based on unchanged levels of mutant load in muscle, morphological findings on muscle biopsy and plasma creatine kinase levels during training, the treatment appears to be safe. Regular, supervised aerobic exercise is therefore recommended in MM patients with the studied mutations.

Oxidative capacity correlates with muscle mutation load in mitochondrial myopathy.

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 (VO(2max)), workload (W(max)), 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%). VO(2max) and W(max) 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.