Short-term aerobic training response in chronic myopathies.

We have previously demonstrated that patients with mitochondrial myopathies can benefit from short-term aerobic exercise training. In this study, we compared the responses to short-term aerobic training of patients with mitochondrial myopathies, patients with nonmetabolic myopathies, and sedentary normal subjects. Training consisted of 8 weeks of treadmill exercise at 70% to 85% of estimated maximum heart rate reserve. All groups showed significant improvements in estimated aerobic capacity as well as heart rate and blood lactate at submaximal exercise intensities. The increase in estimated aerobic capacity was greater in the mitochondrial myopathy patients than in the other two groups. Phosphorus magnetic resonance spectroscopy demonstrated increased oxidative capacity of muscle in patients with mitochondrial myopathies in response to this training but not in patients with other, nonmetabolic myopathies or sedentary control subjects. A self-assessed measurement of functional status (SF-36) suggested improved quality of life associated with the training. This study demonstrates that short-term aerobic training at low intensity can benefit patients with nonmetabolic myopathies but to a lesser extent than patients with mitochondrial myopathies.     

The relationship of plasma catecholamine and lactate during anaerobic threshold exercise in mitochondrial myopathies.

Sympathetic system activation is considered one of the main factors influencing lactate production during exercise in normal individuals. In order to assess the role of such activation in mitochondrial myopathies, we compared blood catecholamine levels to those of lactate during an intermittent exercise performed at workloads near anaerobic lactate threshold. Following an initial increment, the patients (n = 10) exhibited a steady-state blood lactate shifted right relative to controls (n = 7), the peaks being respectively 665 +/- 29% and 322 +/- 11% of baseline. Plasma catecholamine increase in mitochondrial myopathies was 272 +/- 21% for norepinephrine and 261 +/- 18% for epinephrine, not statistically different from controls. Lactate/norepinephrine and lactate/epinephrine area ratios were significantly higher in the subjects than in controls (2.36 versus 1.48 and 2.40 versus 1.57, respectively). The study shows that the abnormal lactate production in mitochondrial myopathies is independent of the catecholaminergic response at the transition from aerobic to anaerobic exercise.     

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.     

Lactate production upon short-term non–ischemic forearm exercise in mitochondrial disorders and other myopathies

BACKGROUND: The nonischemic forearm exercise test (NIFET) has been shown to be as effective as the classic ischemic forearm exercise test (IFET) in the diagnosis of patients with McArdle disease. Recently, the lactate increase normalized to the mechanical energy production in NIFET was suggested to have a intermediate sensitivity and satisfactory specifity for the screening of mitochondrial disorders. METHODS: NIFET at 80% maximal contraction force (MCF) was performed in normal controls (n = 41), patients with mitochondrial disorders (n = 15) and other myopathies (diseased controls, n = 20). 26 healthy volunteers also underwent IFET at 80% MCF. The ratio of lactate increase and workload was defined as specific lactate production (mmol x s/N x l). RESULTS: In normal controls there was no significant different lactate increase during NIFET and IFET. The workload performed showed only a weak significant positive correlation with the lactate increase in the NIFET in normal controls (r(2) = 0.20) but not in IFET and NIFET with patients. A moderate negative correlation of specific lactate production and the absolute workload was found in all groups and in both protocols (r(2) = 0.22-0.34). The specific lactate production was highest in patients with other myopathies, intermediate in patients with mitochondrial disorders and lowest in normal controls. NIFET showed a sensitivity of only 20 % and a specifity of 95% for normal controls, but only 75 % for diseased controls. CONCLUSION: The specific lactate production during NIFET is neither sufficiently specific nor sensitive for the diagnosis of mitochondrial disorders. Increased specific lactate production during rest-to-work transition period might be caused by increased acetyl group deficits.     

Is Parkinson's disease a mitochondrial disorder?

Parkinson's disease (PD) is a common degenerative disease, but its etiology is still unknown. However, since the discovery of MPTP, many investigators have been interested in the mitochondrial function in PD. We investigated mitochondrial functions in PD patients using the methods which have successfully been applied to mitochondrial myopathies (MM), i.e. assay of lactate and pyruvate, measurement of muscle mitochondrial respiratory enzyme activities and Southern blot analysis of muscle mitochondrial DNA. Parkinson's disease patients did not differ from controls in the mean blood and CSF (cerebrospinal fluid) lactate and pyruvate levels at the basal resting state or during an aerobic exercise. But mitochondrial complex I activity of the skeletal muscle was significantly decreased in PD. In the Southern blot analysis, we could not find major deletions or insertions of mitochondrial DNA in PD. Our studies disclosed a differential mitochondrial impairment between PD and MM. We discuss the implication of our observation.     

New approaches for the treatment of metabolic myopathies

Metabolic myopathies are inborn errors of intermediate muscle metabolism, presenting either by exercise intolerance, or by progressive muscle weakness. Growing knowledge concerning the pathophysiology of these rare disorders, and the development of new technologies, opens new avenues for the treatment of this group of myopathies. Recent studies showed improvement in exercise capacity after regular aerobic exercise training in patients with McArdle's disease and mitochondrial myopathies. In late-onset Pompe disease enzyme replacement therapy trials with recombinant acid alpha-glucosidase (Myozyme) are currently in progress, the first trials conducted in childhood onset Pompe disease having previously shown a clear improvement in life expectancy and cardiac function. The demonstration that fibrates can induce correction of carnitine palmitoyl-transferase II deficiency in patients cells, lead to the development of an open-labelled therapeutic trial with bezafibrate in patients with CPTII deficiency, which is actually ongoing.     

Modified exercise test in screening for mitochondrial myopathies--adjustment of workload in relation to muscle strength

The aim of this study was to evaluate the usefulness of a modification of the bicycle ergometer test, the subanaerobic threshold exercise test (SATET), as a screening test for patients with mitochondrial myopathies. Since the original SATET is frequently found to be strenuous for weak patients, a new variable (relative muscle strength) was added to the workload formula. Plasma lactate levels were recorded at rest, then after 5 and 15 min of cycling on an ergometer, with constant workload. Nine patients with mitochondrial myopathy, 10 patients with other neuromuscular diseases and 9 healthy but sedentary volunteers undertook the test. An upper reference limit after exercise for plasma lactate was settled at 2.9 mmol/l. The modified SATET showed a sensitivity of 78% and a specificity compared to the healthy subjects of 100%. Compared to patients with other neuromuscular diseases, the specificity was lower (60%). All subjects completed the test without severe fatigue or pain.     

Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects

Aerobic training has been shown to increase work and oxidative capacity in patients with mitochondrial myopathies, but the mechanisms underlying improvement are not known. We evaluated physiological (cycle exercise, 31P-MRS), biochemical (enzyme levels), and genetic (proportion of mutant/wild-type genomes) responses to 14 weeks of bicycle exercise training in 10 patients with heteroplasmic mitochondrial DNA (mtDNA) mutations. Training increased peak work and oxidative capacities (20-30%), systemic arteriovenous O2 difference (20%), and 31P-MRS indices of metabolic recovery (35%), consistent with enhanced muscle oxidative phosphorylation. Mitochondrial volume in vastus lateralis biopsies increased significantly (50%) and increases in deficient respiratory chain enzymes were found in patients with Complex I (36%) and Complex IV (25%) defects, whereas decreases occurred in 2 patients with Complex III defects (approximately 20%). These results suggest that the cellular basis of improved oxygen utilization is related to training-induced mitochondrial proliferation likely resulting in increased levels of functional, wild-type mtDNA. However, genetic analysis indicated the proportion of wild-type mtDNA was unchanged (3/9) or fell (6/9), suggesting a trend toward preferential proliferation of mutant genomes. The long-term implications of training-induced increases in mutant relative to wild-type mtDNA, despite positive physiological and biochemical findings, need to be assessed before aerobic training can be proposed as a general treatment option.     

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.     

The prolonged exercise test

The response to a standardized exercise test was investigated in 12 volunteers and 13 patients with aches, cramps, and pains. In men, creatine kinase (CK) levels peaked (up to 1600 mU per milliliter) between 10 and 20 hours after exercise. High levels of blood lactate during exercise were related to the intensity of work and to high levels of CK after exercise. The patients could be divided into several groups: (1) those with no change in blood metabolites (psychogenic); (2) those with a disproportionate rise in CK (metabolic myopathies); (3) those with a disproportionate rise of lactate (mitochondrial abnormalities); and (4) in one patient with exercise-related pains, subnormal elevation of fatty acid levels. The correlation of changes in blood lactate, CK, and fatty acids may be useful, whereas an isolated measurement, even if outside the normal range, is often meaningless.     

Aerobic conditioning: an effective therapy in McArdle's disease

OBJECTIVE: Susceptibility to exertional cramps and rhabdomyolysis in myophosphorylase deficiency (McArdle's disease [MD]) may lead patients to shun exercise. However, physical inactivity may worsen exercise intolerance by further reducing the limited oxidative capacity caused by blocked glycogenolysis. We investigated whether aerobic conditioning can safely improve exercise capacity in MD. METHODS: Eight MD patients (4 men and 4 women; age range, 33-61 years) pedalled a cycle ergometer for 30 to 40 minutes a day, 4 days a week, for 14 weeks, at an intensity corresponding to 60 to 70% of maximal heart rate. We monitored serum creatine kinase levels; changes in peak cycle work, oxygen uptake, and cardiac output; presence and magnitude of a spontaneous and glucose-induced second wind; and citrate synthase and beta-hydroxyacyl coenzyme A dehydrogenase enzyme activities in quadriceps muscle. RESULTS: The prescribed exercise program increased average work capacity (36%), oxygen uptake (14%), cardiac output (15%), and citrate synthase and beta-hydroxyacyl coenzyme A dehydrogenase enzyme levels (80 and 62%, respectively) without causing pain or cramping or increasing serum creatine kinase. A spontaneous and glucose-induced second wind was present and was of similar magnitude in each patient before and after training. INTERPRETATION: Moderate aerobic exercise is an effective means of improving exercise capacity in MD by increasing circulatory delivery and mitochondrial metabolism of bloodborne fuels.     

A non-ischemic forearm exercise test for the screening of patients with exercise intolerance.

BACKGROUND: The forearm exercise test is a common investigation that allows detection of some metabolic myopathies. It is not completely standardized and, when performed in ischemic conditions, may induce rhabdomyolysis in patients with glycogenosis. OBJECTIVE: To develop a standardized non-ischemic exercise test for a safe screening of patients with exercise intolerance. METHODS: Twenty-six healthy subjects and 32 patients with exercise intolerance performed an isometric exercise at 70% of the maximal voluntary contraction during 30 seconds in non-ischemic conditions. Blood concentrations of creatine kinase, lactate, and ammonia were analyzed. RESULTS: A nearly fourfold lactate rise was induced by exercise in healthy subjects. All patients with normal muscle biopsy showed values similar to those of healthy subjects. No significant lactate increase was observed in six patients with a myophosphorylase defect and one with a debrancher defect. Disparate lactate responses were observed in 14 patients with a mitochondrial myopathy. The blood lactate level at rest was abnormally high in four of these patients. The lactate surface normalized by the mechanical energy production was above the normal range in eight patients. CONCLUSIONS: The authors propose a standardized non-ischemic grip test that overcomes the main drawbacks of the classic ischemic forearm exercise test. It provides a specific, efficient, and safe screening test for patients with exercise intolerance. Its sensitivity was very good for patients with a glycogenolysis defect but remains partial in patients with a mitochondrial disorder.     

Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis

Multiple sclerosis (MS) patients of an inpatient rehabilitation program have been randomly assigned to an exercise training (MS-ET) or nontraining group (MS-NI). Before and after 4 weeks of aerobic exercise training, a graded maximal exercise test with measurement of gas exchange and a lung function test was administered to all 26 patients fulfilling the inclusion criteria. Activity level, fatigue and health perception were measured by means of questionnaires. Twenty-six healthy persons served as control group and were matched in respect of age, gender and activity level. Training intervention consisted of 5x30 min sessions per week of bicycle exercise with individualised intensity. Compared with baseline, the MS training group demonstrated a significant rightward placement of the aerobic threshold (AT) (VO2+13%; work rate [WR])+11%), an improvement of health perception (vitality+46%; social interaction+36%), an increase of activity level (+17%) and a tendency to less fatigue. No changes were observed for the MS-NI group and the control groups. Maximal aerobic capacity and lung function were not changed by either training or nontraining in all four groups. Overall compliance to the training program was quite low (65%), whereas incidence of symptom exacerbation by physical activity has been lower than expected (6%).     

31P-NMR spectroscopy of mitochondrial myopathies: the relation between abnormal energy metabolism and muscle biopsy findings

31P-NMR spectra were obtained from the quadriceps femoris muscle (at rest and after aerobic exercise) of the 7 cases of mitochondrial myopathies (2 cases of mitochondrial encephalomyopathy and lactic acidosis(MELA), 1 case of myoclonus epilepsy with regged red fiber, 1 case of Kearns-Sayre syndrome, 3 cases of progressive external ophthalmoplegia), using superconducting whole body MR (Magnetom, Siemens). One case showed abnormally low Pcr/Pi ratio in the resting state. An aerobic exercise using ergometer was performed on the other 6 patients. Three of them demonstrated significant reduction and delayed recovery of the Pcr/Pi ratio after exercise. This reduction was not detected in the control subjects. Histological studies of biopsied muscles revealed ragged red fibers in all the cases, the number varies, however, from 0.5 to 15.3 per cent of the total fibers. Abnormalities in the Pcr/Pi ratio of phosphorus spectra, in resting state or after exercise, tend to be observed in patients showing abundant ragged red fibers. Focal cytochrome c oxidase deficiency with relatively small amount of ragged red fibers (less than 10 per cent of the total fibers) was histologically noted in five of our patients, excluding 2 MELA patients. Biochemical assay of mitochondria enzyme was normal. It has been assumed that these patients have no primary defect in energy metabolism and the occasionally observed cytochrome c oxidase deficient fibers are non-specific findings probably caused by some devastating process occurring in these fibers. However, our present studies revealed abnormal reduction and delayed restoration of the Pcr/Pi ratio in 2 out of 5 focal cytochrome c oxidase deficiency cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

不同训练负荷条件下SD大鼠运动模型的构建与评价

背景：目前对运动训练中机体能量代谢的研究多集中于骨骼肌线粒体生物发生及线粒体氧自由基等各指标的变化,不同训练负荷条件下身体能量代谢的系统的机制研究较少。 目的：建立SD大鼠有氧、无氧及有氧无氧代谢交叉训练运动模型,评价各组SD大鼠能量代谢水平指标的变化。 方法：实验建立有氧、无氧、有氧和无氧交替运动SD大鼠跑台运动训练模型,有氧运动时采用递增负荷训练,无氧运动时采用高速间歇训练,并设立正常对照组。测量运动后大鼠体质量减轻程度的变化,检测运动后大鼠血清中乳酸、乳酸脱氢酶、肌酐、尿素氮、肌酸激酶、丙酮酸激酶和琥珀酸脱氢酶的活性。 结果与结论：实验结果显示无氧组体质量减轻程度明显(P < 0.05),乳酸水平增高(P < 0.05),琥珀酸脱氢酶水平低于有氧组(P < 0.05);无氧组和交替运动组乳酸脱氢酶水平均增高(P < 0.05);运动后大鼠尿素氮水平增高非常显著(P < 0.001);交替组肌酸激酶、肌酐水平显著增高(P < 0.01),丙酮酸激酶水平增高(P < 0.05)。结果表明运动后大鼠代谢水平符合有氧、无氧、有氧和无氧交替运动的代谢评价,运动模型构建成功。     

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.     

Multicenter trial with ubidecarenone: treatment of 44 patients with mitochondrial myopathies

Fourty four patients with mitochondrial myopathies were treated with Ubidecarenone (CoQ10) for six months in an open multicentric trial. No side effects due to the drug administration were observed. Sixteen patients showing at least 25% decrease of post exercise lactate levels were selected as responders. Responsiveness was apparently not related to CoQ10 level in serum and platelets or to the presence or absence of mtDNA deletions. The responders were further treated for 3 months with CoQ10 or placebo in the second blind part of the trial; no significant differences between the 2 groups were observed. It is not clear why CoQ10 had therapeutic effects in some patients and not in others with the same clinical presentation and biochemical defect, and we failed to identify candidate responders before treatment. At the dosage of CoQ10 used in the study (2 mg/kg/day) the therapy requires long administration time before a response is demonstrable.     

The relationship between anaerobic lactate threshold and plasma catecholamines during incremental exercise in hereditary spastic paraplegia

Lower limb muscle chronic hyperactivity in hereditary spastic paraplegia (HSP) is the consequence of motor corticospinal tract involvement, which in turn has been hypothesized to be of mitochondrial origin. In order to assess skeletal muscle aerobic metabolism and sympathetic response during exercise in 10 HSP patients, we evaluated their blood lactate and catecholamine levels during an incremental workload bicycle exercise. Lactate, but not epinephrine or norepinephrine, levels were significantly higher in the HSP patients than in control subjects, in both resting conditions and during exercise. In the patients, the anaerobic lactate threshold was reached prematurely (at 50% of the predicted normal maximal power output) when compared to normal controls. This finding was not related to any specific muscle morphology or histochemical activity. Although other factors, including chronic spasticity and muscle deconditioning, have to be considered in the interpretation of our data, our results suggest the possible involvement of a mitochondrial mechanism, independently of sympathetic system overactivation, in exercising skeletal muscle of HSP patients.     

A randomized trial of coenzyme Q10 in mitochondrial disorders

Case reports and open-label studies suggest that coenzyme Q(10) (CoQ(10)) treatment may have beneficial effects in mitochondrial disease patients; however, controlled trials are warranted to clinically prove its effectiveness. Thirty patients with mitochondrial cytopathy received 1200 mg/day CoQ(10) for 60 days in a randomized, double-blind, cross-over trial. Blood lactate, urinary markers of oxidative stress, body composition, activities of daily living, quality of life, forearm handgrip strength and oxygen desaturation, cycle exercise cardiorespiratory variables, and brain metabolites were measured. CoQ(10) treatment attenuated the rise in lactate after cycle ergometry, increased (∽1.93 ml) VO(2)/kg lean mass after 5 minutes of cycling (P < 0.005), and decreased gray matter choline-containing compounds (P < 0.05). Sixty days of moderate- to high-dose CoQ(10) treatment had minor effects on cycle exercise aerobic capacity and post-exercise lactate but did not affect other clinically relevant variables such as strength or resting lactate.