Physical capacity,respiratory quotient and energy expenditure during exercise in male patients with schizophrenia compared with healthy controls

BackgroundDespite massive research on weight gain and metabolic complications in schizophrenia there are few studies on energy expenditure and no current data on physical capacity.AimTo determine oxygen uptake capacity, respiratory quotient (RQ) and energy expenditure during a submaximal exercise test in patients with schizophrenia and healthy controls.MethodTen male patients and 10 controls were included. RQ and energy expenditure were investigated with indirect calorimetry during a cycle ergometer test. The submaximal work level was defined by heart rate and perceived exhaustion. Physical capacity was determined from predicted maximal oxygen uptake capacity (VO_2-max).ResultsThe patients exhibited significantly higher RQ on submaximal workloads and lower physical capacity. A significant lower calculated VO_2-max remained after correction for body weight and fat free mass (FFM). Energy expenditure did not differ on fixed workloads.ConclusionRQ was rapidly increasing in the patients during exercise indicating a faster transition to carbohydrate oxidation and anaerobic metabolism that also implies a performance closer to maximal oxygen uptake even at submaximal loads. This may restrict the capacity for everyday activity and exercise and thus contribute to the risk for weight gain. Physical capacity was consequently significantly lower in the patients.     

Low anaerobic threshold and increased skeletal muscle lactate production in subjects with Huntington's disease

Mitochondrial defects that affect cellular energy metabolism have long been implicated in the etiology of Huntington's disease (HD). Indeed, several studies have found defects in the mitochondrial functions of the central nervous system and peripheral tissues of HD patients. In this study, we investigated the in vivo oxidative metabolism of exercising muscle in HD patients. Ventilatory and cardiometabolic parameters and plasma lactate concentrations were monitored during incremental cardiopulmonary exercise in twenty‐five HD subjects and twenty‐five healthy subjects. The total exercise capacity was normal in HD subjects but notably the HD patients and presymptomatic mutation carriers had a lower anaerobic threshold than the control subjects. The low anaerobic threshold of HD patients was associated with an increase in the concentration of plasma lactate. We also analyzed in vitro muscular cell cultures and found that HD cells produce more lactate than the cells of healthy subjects. Finally, we analyzed skeletal muscle samples by electron microscopy and we observed striking mitochondrial structural abnormalities in two out of seven HD subjects. Our findings confirm mitochondrial abnormalities in HD patients' skeletal muscle and suggest that the mitochondrial dysfunction is reflected functionally in a low anaerobic threshold and an increased lactate synthesis during intense physical exercise. © 2010 Movement Disorder Society     

Decreased platelet cytochrome c oxidase activity is accompanied by increased blood lactate concentration during exercise in patients with Alzheimer disease

Increasing evidence indicates that mitochondrial dysfunction occurs in the central nervous system as well as in the peripheral tissues from Alzheimer's disease (AD) patients. We have recently shown that mitochondrial cytochrome c oxidase (COX) activity is significantly reduced in brain and platelets from AD patients compared to controls. In the present study we investigated whether impaired COX activity could have functional consequences on energy metabolism. Blood lactate concentration was monitored at rest and during incremental exercise in 22 AD patients in whom COX activity in platelets was decreased compared to controls (35.7 +/- 11.4 vs 48.4 +/- 1.4 nmol/min/mg, P < 0.01). In both resting and exercising conditions, blood lactate was significantly higher in AD patients than in controls. Although the magnitude of exercise-related lactate accumulation was not different between the two groups, an anticipated anaerobic lactate threshold during the incremental forearm exercise was found in AD patients (50% of maximal voluntary contraction MVC compared to 60% in controls). COX activity was inversely related to lactate at a significant level for resting condition (r = -0.65) and borderline for anaerobic threshold exercise level. These results support the hypothesis of a systemic impairment of the mitochondrial function in AD and indicate that decreased COX activity could have functional consequences on metabolism.     

Venous oxygen levels during aerobic forearm exercise: An index of impaired oxidative metabolism in mitochondrial myopathy.

A cardinal feature of impaired skeletal muscle oxidative metabolism in mitochondrial myopathies is a limited ability to increase the extraction of O(2) from blood relative to the increase in O(2) delivery by the circulation during exercise. We investigated whether aerobic forearm exercise would result in an abnormal increase in venous effluent O(2) in patients with impaired skeletal muscle oxidative phosphorylation attributable to mitochondrial disease. We monitored the partial pressure of O(2) (PO(2)) in cubital venous blood at rest, during handgrip exercise, and during recovery in 13 patients with mitochondrial myopathy and exercise intolerance and in 13 healthy control and 11 patient control subjects. Resting and recovery venous effluent PO(2) were similar in all subjects, but during exercise venous PO(2) paradoxically rose in mitochondrial myopathy patients from 27.2 +/- 4.0mmHg to 38.2 +/- 13.3mmHg, whereas PO(2) fell from 27.2 +/- 4.2mmHg to 24.2 +/- 2.7mmHg in healthy subjects and from 27.4 +/- 9.5mmHg to 22.2 +/- 5.2mmHg in patient controls. The range of elevated venous PO(2) during forearm exercise in mitochondrial myopathy patients (32 to 82mmHg) correlated closely with the severity of oxidative impairment as assessed during cycle exercise. We conclude that measurement of venous PO(2) during aerobic forearm exercise provides an easily performed screening test that sensitively detects impaired O(2) use and accurately assesses the severity of oxidative impairment in patients with mitochondrial myopathy and exercise intolerance.     

<Superscript>31</Superscript>P-MRS of skeletal muscle is not a sensitive diagnostic test for mitochondrial myopathy

Clinical phenotypes of persons with mitochondrial DNA (mtDNA) mutations vary considerably. Therefore, diagnosing mitochondrial myopathy (MM) patients can be challenging and warrants diagnostic guidelines. (31)phosphorous magnetic resonance spectroscopy ((31)P-MRS) have been included as a minor diagnostic criterion for MM but the diagnostic strength of this test has not been compared with that of other commonly used diagnostic procedures for MM. To investigate this, we studied seven patients with single, large-scale deletions-, nine with point mutations of mtDNA and 14 healthy subjects, who were investigated for the following: 1) (31)P-MRS of lower arm and leg muscles before and after exercise, 2) resting and peak-exercise induced increases of plasma lactate, 3) muscle morphology and -mitochondrial enzyme activity, 4) maximal oxygen uptake (VO(2max)), 5) venous oxygen desaturation during handgrip exercise and 6) a neurological examination. All MM patients had clinical symptoms of MM, > 2% ragged red fibers in muscle, and impaired oxygen desaturation during handgrip. Fourteen of 16 patients had impaired VO(2max), 10/16 had elevated resting plasma lactate, and 10/11 that were investigated had impaired citrate synthase-corrected complex I activity. Resting PCr/P(i) ratio and leg P(i) recovery were lower in MM patients vs. healthy subjects. PCr and ATP production after exercise were similar in patients and healthy subjects. Although the specificity for MM of some (31)P-MRS variables was as high as 100%, the sensitivity was low (0-63%) and the diagnostic strength of (31)P-MRS was inferior to the other diagnostic tests for MM. Thus, (31)P-MRS should not be a routine test for MM, but may be an important research tool.     

Lactate increase and oxygen desaturation in mitochondrial disorders – Evaluation of two diagnostic screening protocols

Background Mitochondrial disorders are characterized by an accumulation of lactate and an insufficient oxygen extraction from blood during exercise. Therefore, both parameters (lactate and oxygen saturation) can be used as screening tests in mitochondrial disorders. However, conflicting results regarding sensitivities and specifities of both tests have been reported. Method We examined 27 patients with genetically defined mitochondrial disorders (single deletions n = 15,multiple deletions n = 5, A3243G mutation n = 7), patients with other neuromuscular disorders, and healthy controls. In the first test subjects performed intermittent isometric handgrip exercise (0.5 Hz) at 80 % (3 minutes) and 30 % (3 and 15 minutes) of maximal contraction force (MCF). Oxygen saturation and partial pressure in cubital venous blood from the exercising arm were measured. In the second test subjects underwent cycle ergometry at 30 W for 15 minutes. Venous lactate at rest, during and 15 minutes postexercise was determined. Result Both tests showed specificities of 92–96%. Sensitivities for changes of venous oxygen partial pressure and oxygen saturation ranged from 21–26% at 80% MCF for 3 minutes to 47–58% at 30% MCF for 15 minutes. Sensitivities for venous resting, peak, and post–exercise lactate was 33%, 58%, and 67%, respectively. The degree of deoxygenation, however,was independent of the intensity and duration of the applied forces. Oxygen desaturation and lactate increase in patients with mitochondrial disorders were not different in patients with and without clinical symptoms of myopathy. There were significant correlations between the heteroplasmy and both the degree of oxygen desaturation and lactate increase in patients with single deletions. In patients who performed both protocols (n = 16) a combination of both tests increased sensitivity up to 87%. Conclusion Oxygen desaturation in forearm exercise tests and lactate increase in cycle ergometry tests show a high specifity but only moderate sensitivity. Combination of the two screening test clearly increases the sensitivity.     

Monitoring of ventilation during the early part of cardiopulmonary exercise testing: the first step to detect central sleep apnoea in chronic heart failure

BACKGROUND AND PURPOSE: To evaluate the prediction of nocturnal central sleep apnoea (CSA) syndrome from the presence of periodic breathing (PB) on diurnal monitoring of pre-exercise (cardiopulmonary exercise test [CPX]) parameters. CSA syndrome is commonly found in congestive heart failure (CHF) patients and has several prognostic and therapeutic implications but is frequently undiagnosed. Awake PB pattern is sometimes observed during the CPX cardiopulmonary monitoring period of gas exchanges in CHF patients referred to the stress test laboratory for routine peak VO2 determination. PATIENTS AND METHODS: Forty-five consecutive ambulatory patients (2 women/43 men; 60.2+/-11.7 years old) with clinically moderate to severe CHF (New York Heart Association [NYHA] class II/III: 22/23; mean+/-standard deviation left ventricular ejection fraction [LVEF]: 30.5+/-6.6%) underwent a classical maximal CPX test including a 2-min period (pre-test) of gas exchange monitoring and nocturnal ambulatory polygraphic monitoring. PB was defined when a cyclical pattern of VE, VO2, VCO2, was visually noted during the pre-exercise period and/or during the first 4 min of the CPX. CSA syndrome was retained as a central apnoea-plus-hypopnea index (cAHI) equal to or more than 10/h. The sleep study scoring procedure was done independently of the knowledge of the CPX results. Sensitivity, specificity and predictive values were calculated and receiver operating characteristic (ROC) curve analysis was constructed. RESULTS: Peak VO2 reached 16.4+/-5.2 mL kg(-1)min(-1) (55% of the theoretical value adjusted for gender and age). The polygraphy was completed and validated (at least five consecutive hours of sleep) in all cases. CSA syndrome was found in 28 (62%) patients (mean cAHI: 19.3+/-8.6/h). Sensitivity for the prediction of CSA syndrome reached 92.9% (two false-negative patients with a cAHI of nine) and specificity 94.1% with a predictive accuracy of 93.3%. The only false-positive patient suffered a moderate but significant obstructive sleep apnoea syndrome. Using ROC curve analysis, the W value reached 0.99 for the prediction of CSA from the presence of PB. The presence of CSA syndrome, using logistic regression analysis, is associated with a more severe functional status (NYHA: p<0.01, peak VO2: p<0.002), a lower basal and peak end-expiratory CO2 pressure (PETCO2, all p<0.03), a worse LVEF (p<0.01) and age equal to or more than 60 years (p<0.03). CONCLUSIONS: The observation of PB in the preliminary period of the CPX test in CHF patients appeared highly predictive of the presence of CSA syndrome during sleep and could prompt the use of polygraphic monitoring in severe CHF patients.     

Exercise training in mitochondrial myopathy: a randomized controlled trial

Patients with mitochondrial myopathies (MM) usually suffer from exercise intolerance due to their impaired oxidative capacity and physical deconditioning. We evaluated the effects of a 12-week supervised randomized rehabilitation program involving endurance training in patients with MM. Twenty MM patients were assigned to a training or control group. For three nonconsecutive days each week, patients combined cycle exercise at 70% of their peak work rate with three upper-body weight-lifting exercises performed at 50% of maximum capacity. Training increased maximal oxygen uptake (28.5%), work output (15.5%), and minute ventilation (40%), endurance performance (62%), walking distance in shuttle walking test (+95 m), and peripheral muscle strength (32%-62%), and improved Nottingham Health Profile scores (21.47%) and clinical symptoms. Control MM patients did not change from baseline. Results show that our exercise program is an adequate training strategy for patients with mitochondrial myopathy.     

Abnormal in vivo skeletal muscle energy metabolism in Huntington's disease and dentatorubropallidoluysian atrophy

We studied in vivo muscle energy metabolism in patients with Huntington's disease (HD) and dentatorubropallidoluysian atrophy (DRPLA) using 31P magnetic resonance spectroscopy (MRS). Twelve gene-positive HP patients (4 presymptomatic patients) and 2 gene-positive DRPLA patients (1 presymptomatic patient) were studied. 31P-MRS at rest showed a reduced phosphocreatine-to-inorganic phosphate ratio in the symptomatic HD patients and DRPLA patient. Muscle adenosine triphosphate/(phosphocreatine + inorganic phosphate) at rest was significantly reduced in both groups of symptomatic and presymptomatic HD subjects and was below the normal range in the 2 DRPLA subjects. During recovery from exercise, the maximum rate of mitochondrial adenosine triphosphate production was reduced by 44% in symptomatic HD patients and by 35% in presymptomatic HD carriers. The maximum rate of mitochondrial adenosine triphosphate production in muscle was also reduced by around 46% in the 2 DRPLA subjects. Our findings show that HD and DRPLA share a deficit of in vivo mitochondrial oxidative metabolism, supporting a role for mitochondrial dysfunction as a factor involved in the pathogenesis of these polyglutamine repeat-mediated neurodegenerative disorders. The identification of 31P-MRS abnormalities may offer a surrogate biochemical marker by which to study disease progression and the effects of treatment in HD and DRPLA.     

Brain nonoxidative carbohydrate consumption is not explained by export of an unknown carbon source: evaluation of the arterial and jugular venous metabolome

Brain activation provokes nonoxidative carbohydrate consumption and during exercise it is dominated by the cerebral uptake of lactate resulting in that up to ∼1 mmol/ 100 g of glucose equivalents cannot be accounted for by cerebral oxygen uptake. The fate of this ‘extra'' carbohydrate uptake is unknown, but it may be that brain metabolism is balanced by a yet-unidentified substance(s). This study used a nuclear magnetic resonance-based metabolomics approach to plasma samples obtained from the brachial artery and the right internal jugular vein in 16 healthy young males to identify carbon species going to and from the brain. We observed a carbohydrate accumulation of 255±37 μmol/100 g glucose equivalents at exhaustion not accounted for by the oxygen uptake. Although the cumulated uptake was lower than earlier observed, the results show that glucose and lactate are responsible for the majority of the carbon exchange across the brain. Even during intense exercise associated with the largest nonoxidative carbohydrate consumption, the brain did not show significant release of any other metabolite. We conclude that during exercise, the surplus carbohydrate uptake by the brain cannot be accounted for by changes in the NMR-derived plasma metabolome across the brain.     

Evaluation of physical fitness parameters in patients with schizophrenia

The aims of this study were to compare aerobic and anaerobic exercise capacities, pulmonary functions, body composition and fat distribution parameters in patients with schizophrenia and healthy controls and to investigate the associations among these parameters. Sixty (30 male, 30 female) patients with schizophrenia and 60 (30 male, 30 female) healthy controls were included in the study. Maximal aerobic capacity was estimated with the Astrand submaximal exercise protocol, and anaerobic performance was determined with a Wingate test. Body composition was established with a bioelectrical impedance analyzer. Pulmonary function tests, skinfold thickness and body circumference measurements were also carried out. Maximal aerobic capacity, maximal anaerobic power, anaerobic capacity and pulmonary function tests (forced vital capacity and maximal voluntary ventilation) were found to be lower in male and female schizophrenic groups as compared to the controls. Body fat percentage, waist and abdomen circumferences, and waist to hip ratio were found to be higher in female schizophrenic patients than in controls. We suggest that maximal aerobic capacity, maximal anaerobic power, and anaerobic capacity are poor in the schizophrenia patients as compared to healthy controls. Low cardiorespiratory fitness is related to reduced pulmonary function and impaired body composition in schizophrenia patients.     

Myophosphorylase deficiency impairs muscle oxidative metabolism

We studied oxidative metabolism during bicycle exercise in 4 patients with myophosphorylase deficiency. Maximal oxygen uptake (VO2max) was low (14.0 +/- 1.4 ml X kg-1 X min-1, mean +/- SE) compared with that in normal subjects (37.7 +/- 1.9; n = 12) and patients with myalgia (24.9 +/- 1.8; n = 10). Carbohydrate oxidation, as estimated by the respiratory exchange ratio (R), was low relative to workload (max R, mean +/- SE: McArdle's disease, 0.96 +/- 0.02; normal subjects, 1.13 +/- 0.02; myalgia, 1.09 +/- 0.02). Intravenous glucose administration increased maximal oxygen uptake about 20% in those with McArdle's disease, but both VO2max and R remained lower than in control subjects. These findings suggest that the capacity for dynamic exercise in McArdle's disease is limited by the availability of oxidative substrate, and indicate that blood glucose is unable to substitute fully for muscle glycogen as an oxidative fuel. We also found that exercise cardiac output (Q) was excessive relative to oxygen uptake in affected patients (delta Q/delta VO2, mean +/- SE: McArdle's disease, 11.6 +/- 1.7; normal subjects, 4.8 +/- 0.2; myalgia, 5.6 +/- 0.2). This hyperkinetic circulation in exercise may serve to increase the delivery of blood-borne oxidative substrate to working muscle.     

Resting oxygen consumption and in vivo ADP are increased in myopathy due to complex I deficiency

BACKGROUND: Patients with isolated complex I deficiency (CID) in skeletal muscle mitochondria often present with exercise intolerance as their major clinical symptom. OBJECTIVE: To study the in vivo bioenergetics in patients with complex I deficiency in skeletal muscle mitochondria. METHODS: In vivo bioenergetics were studied in three of these patients by measuring oxygen uptake at rest and during maximal exercise, together with forearm ADP concentrations ([ADP]) at rest. Whole-body oxygen consumption at rest (VO(2)) was measured with respiratory calorimetry. Maximal oxygen uptake (VO(2)max) was measured during maximal exercise on a cycle ergometer. Resting [ADP] was estimated from in vivo (31)P MRS measurements of inorganic phosphate, phosphocreatine, and ATP content of forearm muscle. RESULTS: Resting VO(2) was significantly increased in all three patients: 128 +/- 14% (SD) of values in healthy control subjects. VO(2)max in patients was on average 2.8 times their VO(2) at rest and was only 28% of VO(2)max in control subjects. Resting [ADP] in forearm muscle was significantly increased compared with healthy control subjects (patients 26 +/- 2 microM, healthy controls 9 +/- 2 microM). CONCLUSION: In patients with CID, the increased whole-body oxygen consumption rate at rest reflects increased electron transport through the respiratory chain, driven by a decreased phosphorylation potential. The increased electron transport rate may compensate for the decreased efficiency of oxidative phosphorylation (phosphorylation potential).     

Resistance to ischaemic nerve-fibre block in diabetes mellitus and in mitochondrial encephalomyopathies

Thermal thresholds were measured during ischaemic compression block in the left forearms of 26 healthy subjects, 10 patients with diabetes mellitus and 6 patients suffering from different kinds of mitochondrial disorders. Cold and warm thresholds in the 6 patients with deficiencies in the respiratory chain increased earlier than in normals. When cold perception was impaired, cold stimuli were perceived as warmth and pinprick perception attenuated. In diabetics cold thresholds were less elevated during ischaemic block than in controls. This was paralleled by tingling paraesthesiae in all groups. The findings show that higher resistance to ischaemic nerve-fibre block in diabetes mellitus is not exclusively based on increased anaerobic metabolism.     

31P NMR spectroscopy and ergometer exercise test as evidence for muscle oxidative performance improvement with coenzyme Q in mitochondrial myopathies.

Two patients with mitochondrial encephalomyopathy due to complexes I and IV deficiencies received 150 mg/d of coenzyme Q10 (CoQ). We studied them with a bicycle ergometer exercise test and 31P NMR spectroscopy before and after 10 months of treatment. Before treatment, we observed a low phosphocreatine/inorganic phosphate (PCr/P(i)) resting value along with abnormally high resting lactate concentration. During exercise, there was a pronounced acidosis with delayed kinetics of postexercise recovery for blood lactate, pH, PCr, and PCr/P(i) ratio. Oxygen uptake during exercise was reduced while the lowering of the ventilatory threshold indicated an early activation of glycolysis. After treatment, the bicycle ergometer exercise test indicated a significant improvement with a decrease in resting blood lactate level, an increase in oxygen consumption during exercise, and an increase in the kinetics of lactate disappearance during the recovery period. A shift of the ventilatory threshold to higher workload was present. 31P NMR spectroscopy confirmed the improvement, showing a significant increase in the PCr/P(i) ratio at rest and in the kinetics of recovery for pH, PCr, and PCr/P(i) ratio following exercise in patient 1. For patient 2, we observed a less pronounced acidosis correlated with a lesser amount of Pi produced during exercise. These observations indicate an improvement of mitochondrial function and a shift from high to low glycolytic activity in both patients consequent to CoQ treatment.     

Pyruvate dehydrogenase complex: metabolic link to ischemic brain injury and target of oxidative stress

The mammalian pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme complex (greater than 7 million Daltons) that catalyzes the oxidative decarboxylation of pyruvate to form acetyl CoA, nicotinamide adenine dinucleotide (the reduced form, NADH), and CO(2). This reaction constitutes the bridge between anaerobic and aerobic cerebral energy metabolism. PDHC enzyme activity and immunoreactivity are lost in selectively vulnerable neurons after cerebral ischemia and reperfusion. Evidence from experiments carried out in vitro suggests that reperfusion-dependent loss of activity is caused by oxidative protein modifications. Impaired enzyme activity may explain the reduced cerebral glucose and oxygen consumption that occurs after cerebral ischemia. This hypothesis is supported by the hyperoxidation of mitochondrial electron transport chain components and NAD(H) that occurs during reperfusion, indicating that NADH production, rather than utilization, is rate limiting. Additional support comes from the findings that immediate postischemic administration of acetyl-L-carnitine both reduces brain lactate/pyruvate ratios and improves neurologic outcome after cardiac arrest in animals. As acetyl-L-carnitine is converted to acetyl CoA, the product of the PDHC reaction, it follows that impaired production of NADH is due to reduced activity of either PDHC or one or more steps in glycolysis. Impaired cerebral energy metabolism and PDHC activity are associated also with neurodegenerative disorders including Alzheimer's disease and Wernicke-Korsakoff syndrome, suggesting that this enzyme is an important link in the pathophysiology of both acute brain injury and chronic neurodegeneration.     

Demonstration of hyperaccumulation of [18F]2-fluoro-2-deoxy-D-glucose under oxygen deprivation in living brain slices using bioradiography

To clarify the mechanism of hyperaccumulation of glucose in acute brain ischemia by PET, changes of glucose metabolism and mitochondrial electron transfer function were examined in living brain slices in vitro during control, hypoxic, and anoxic conditions by positron autoradiography using [(18)F]2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) and [(15)O]oxygen. [(15)O]Oxygen fixation reflecting mitochondrial electron transfer function was reduced and [(18)F]FDG uptake reflecting glucose metabolism was increased in proportion to the strength of oxygen deprivation during anoxia and hypoxia. Mitochondrial electron transfer function decreased with no regional differences, whereas the glucose metabolism was the most enhanced in the hippocampus and thalamus. The enhanced glucose metabolism was associated with an increased glutamate efflux after hypoxia and anoxia. Glucose metabolism was also increased by the addition of glutamate and was attenuated by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 in the hippocampus and thalamus. The hyperaccumulation of glucose in acute brain ischemia was demonstrated in living brain slices using bioradiography with reduced mitochondrial electron transfer. The activation of NMDA receptors by glutamate during acute brain ischemia might be responsible for hyperutilization of glucose in the hippocampus and thalamus.     

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.     

A forearm exercise screening test for mitochondrial myopathy

BACKGROUND: The authors hypothesized that impaired oxygen extraction in mitochondrial myopathy (MM) results in a high oxygen saturation in venous effluent blood from working muscle and that this phenomenon can be used as a diagnostic tool for MM. METHODS: Twelve patients with MM, 10 patients with muscular dystrophy, and 12 healthy subjects were studied. All subjects performed intermittent static handgrip exercise (1/2 Hz) at 40% of maximal voluntary contraction (MVC) for 3 minutes. Cubital venous oxygen saturation and brachial artery flow were measured in the exercised arm. RESULTS: Exercise-induced venous oxygen desaturation was smaller in patients with MM (Delta - 7 +/- 5%) than in subjects with muscular dystrophy (Delta - 38 +/- 2%; p = 0.00001) and healthy subjects (Delta - 43 +/- 2%; p = 0.0000002). MVC and exercise blood flow were similar in patients with MM (18 +/- 3 kg; 436 +/- 65 mL/min) and patients with muscular dystrophy (15 +/- 3 kg; 460 +/- 85 mL/min), but were higher in healthy subjects (32 +/- 4 kg; 630 +/- 58 mL/min; p < 0.03). In seven patients with MM and seven patients with McArdle disease, studied with a slightly different protocol, exercise-induced oxygen desaturation was also impaired in MM (Delta - +/- 5%) compared with McArdle disease (Delta - 26 +/- 3%; p = 0.007). CONCLUSION: Oxygen desaturation in venous blood from exercising muscle is markedly lower in patients with mitochondrial myopathy than in subjects with other muscle diseases and healthy subjects, suggesting that a forearm exercise test can be a diagnostic screening tool for mitochondrial myopathy.     

Abnormal ventilation during exercise in McArdle's syndrome: modulation by substrate availability

We evaluated ventilation during cycle exercise in four men lacking myophosphorylase. In submaximal exercise of similar relative intensity, ventilation was higher relative to oxygen uptake in McArdle patients than in normal men. The exercise ventilatory response returned to normal after glucose infusion, by fasting to increase free fatty acid availability or by combining fasting and submaximal exercise. Excessive ventilation in exercise was potentiated by inhibiting lipolysis with nicotinic acid. The excessive ventilatory effort and resultant respiratory alkalosis may contribute to exercise intolerance.