Effects of aerobic training on lactate and catecholaminergic exercise responses in mitochondrial myopathies

The aim of this study was to evaluate the effects of an aerobic training program on the metabolic and sympathetic responses to exercise in 12 patients with mitochondrial myopathies. A 10-week course of aerobic training, consisting of supervised exercise every other day on an electrically braked pedal-rate bicycle ergometer was prescribed to each patient and four healthy controls. Venous lactate, epinephrine (EP) and norepinephrine (NEP) levels were assessed at baseline and after the aerobic training by means of constant-workload exercise performed at near lactate threshold (LT). In patients, a decrease in exercise peak values, significant for lactate (-38.6%, P < 0.01) but not for catecholamines (EP: -26.0%, NEP: -22.1%) was observed after training, findings confirmed by the lactate/EP and lactate/NEP area ratios. The results show that lactate accumulation during exercise is decreased after aerobic training in mitochondrial myopathies and that the effect is partially dissociated from the catecholaminergic response. This in turn suggests that the lactate decrease can be explained, at least in part, by the improved muscle oxidative metabolism consequent to the proposed training program.     

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.     

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.     

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.     

Strength and physiological response to exercise in patients with chronic fatigue syndrome

OBJECTIVE: To measure strength, aerobic exercise capacity and efficiency, and functional incapacity in patients with chronic fatigue syndrome (CFS) who do not have a current psychiatric disorder. METHODS: Sixty six patients with CFS without a current psychiatric disorder, 30 healthy but sedentary controls, and 15 patients with a current major depressive disorder were recruited into the study. Exercise capacity and efficiency were assessed by monitoring peak and submaximal oxygen uptake, heart rate, blood lactate, duration of exercise, and perceived exertion during a treadmill walking test. Strength was measured using twitch interpolated voluntary isometric quadriceps contractions. Symptomatic measures included physical and mental fatigue, mood, sleep, somatic amplification, and functional incapacity. RESULTS: Compared with sedentary controls, patients with CFS were physically weaker, had a significantly reduced exercise capacity, and perceived greater effort during exercise, but were equally unfit. Compared with depressed controls, patients with CFS had significantly higher submaximal oxygen uptakes during exercise, were weaker, and perceived greater physical fatigue and incapacity. Multiple regression models suggested that exercise incapacity in CFS was related to quadriceps muscle weakness, increased cardiovascular response to exercise, and body mass index. The best model of the increased exercise capacity found after graded exercise therapy consisted of a reduction in submaximal heart rate response to exercise. CONCLUSIONS: Patients with CFS were weaker than sedentary and depressed controls and as unfit as sedentary controls. Low exercise capacity in patients with CFS was related to quadriceps muscle weakness, low physical fitness, and a high body mass ratio. Improved physical fitness after treatment was associated with increased exercise capacity. These data imply that physical deconditioning helps to maintain physical disability in CFS and that a treatment designed to reverse deconditioning helps to improve physical function.     

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.     

Effects of exercise and weight loss on depressive symptoms among men and women with hypertension

OBJECTIVE: This study aimed to investigate changes in depressive symptoms in hypertensive individuals participating in an exercise and weight loss intervention. METHODS: This study involved 133 sedentary men and women with high blood pressure (BP; 130-180 mmHg systolic BP and/or 85-110 mmHg diastolic BP) who participated in a 6-month intervention consisting of three groups: aerobic exercise, aerobic exercise and weight loss, and a waiting list control. RESULTS: Participants in both treatment groups demonstrated significant improvements in aerobic capacity and lower BP compared with participants in the control group. Participants in the active treatment groups who had mild to moderate depressive symptoms at baseline also exhibited greater reductions in depressive symptoms compared with participants in the control group. CONCLUSION: Results from the present study suggest that exercise, alone or combined with weight management, may reduce self-reported depressive symptoms among patients with hypertension.     

The effects of exercise training on mental well-being in the normal population: a controlled trial

This study was designed to compare the effects of two aerobic training programmes of differing intensities on mood and mental well-being with those of a credible attention-placebo condition. One hundred and nine sedentary adult volunteers from the local population were assigned to four conditions: high intensity aerobic training, moderate intensity aerobic training, attention-placebo and waiting list. Training was carried out over a 10 week period. Subjects were assessed before and after training with psychological measures and the 12 min walk-run test, and follow-up evaluations were undertaken after 3 months. Ninety-four subjects began the programme and the adherence rate averaged 80%, with no significant differences in number of drop-outs between conditions. Appropriate changes in estimated maximum oxygen consumption were observed in the three active conditions with the 12 min walk-run test. Psychological benefits were seen with the moderate exercise condition but not in the high exercise or attention-placebo conditions. These effects were manifest immediately after training on measures of tension/anxiety and confusion, and at follow-up on measures of perceived coping ability. The mechanisms underlying this pattern of results are discussed and the relative importance for health of vigorous activity and physical fitness is considered.     

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)     

Impact of exercise training on plasma adrenocorticotropin response to a well-learned vigilance task

Plasma adrenocorticotropin hormone (ACTH), cortisol, heart rate, self-reported state anxiety and total reaction time responses in physically active (n=8) and sedentary (n=11) middle-aged men were compared during performance of a well-learned, psychologically challenging task. The groups were similar in age (active: 39.9±8.4 yr vs. sedentary: 44.4±7.2 yr) and trait anxiety (29.4±5.2 vs. 34.5±12.6), but they had different maximal oxygen consumption relative to lean body weight (68.6±7.1 vs. 44.7±4.6 ml · kg⁻¹ · min⁻¹). During performance of the psychological protocol, the total group had significant increases in heart rate and state anxiety, whereas both ACTH and cortisol remained near baseline levels. ACTH and cortisol were not different between the groups. The sedentary group exercise trained for 4 mo, which resulted in an 18% improvement in maximal aerobic capacity ( O₂ max). Exercise intervention did not significantly alter the neuroendocrine response compared to pre-training values or compared to a corresponding control group. These findings suggest that enhanced cardiovascular fitness resulting from exercise training does not affect anterior pituitary-adrenocortical activity during performance of a practiced vigilance task.     

Comparison of the effects of acute and regular exercise on intraocular pressure in Turkish athlete and sedentarians

The aim of this study was to investigate the changes that take place in IOP in athletes and people leading sedentary lives subjected to aerobic and anaerobic exercise and how chronic exercise could affect these changes. The study included 20 sportsmen (Group 1), and 20 people leading sedentary lives (Group 2). The intensity of the exercise for both groups was determined according to the Karvonen protocol and executed as an aerobic exercise program involving running on a treadmill for 30 min. Subjects in both groups were subjected to anaerobic exercise according to the Wingate test protocol for 30 s. The intraocular pressure of all subjects before exercise and after aerobic and anaerobic exercise were measured. The IOP before and after exercise aerobic and anaerobic were evaluated by the Willcoxon test whereas the right and left IOP before exercise and after the aerobic and anaerobic exercise programs in both groups were evaluated using the Mann Whitney U test. p values of <.05 were considered significant. Significant differences were found when the pre-exercise and post-aerobic and anaerobic exercise IOPs of the groups were compared (p < .05). Comparison of the post-anaerobic and aerobic exercise revealed a fall in the IOPs of the subjects after the aerobic exercise (p < .01). In this study, exercise was found to lead to a fall in the IOP in both sportsmen and those leading sedentary lives with the fall less apparent under anaerobic conditions than under aerobic conditions. In conclusion, therefore, it can be said that in those with an increased intraocular pressure, regular, moderately intense aerobic exercise rather than short-lived intense exercise could be more useful.     

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.     

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.     

COMPARISON OF THE EFFECTS OF ACUTE AND REGULAR EXERCISE ON INTRAOCULAR PRESSURE IN TURKISH ATHLETE AND SEDENTARIANS

The aim of this study was to investigate the changes that take place in IOP in athletes and people leading sedentary lives subjected to aerobic and anaerobic exercise and how chronic exercise could affect these changes. The study included 20 sportsmen (Group 1), and 20 people leading sedentary lives (Group 2). The intensity of the exercise for both groups was determined according to the Karvonen protocol and executed as an aerobic exercise program involving running on a treadmill for 30 min. Subjects in both groups were subjected to anaerobic exercise according to the Wingate test protocol for 30 s. The intraocular pressure of all subjects before exercise and after aerobic and anaerobic exercise were measured. The IOP before and after exercise aerobic and anaerobic were evaluated by the Willcoxon test whereas the right and left IOP before exercise and after the aerobic and anaerobic exercise programs in both groups were evaluated using the Mann Whitney U test. p values of <.05 were considered significant. Significant differences were found when the pre-exercise and post-aerobic and anaerobic exercise IOPs of the groups were compared (p < .05). Comparison of the post-anaerobic and aerobic exercise revealed a fall in the IOPs of the subjects after the aerobic exercise (p < .01). In this study, exercise was found to lead to a fall in the IOP in both sportsmen and those leading sedentary lives with the fall less apparent under anaerobic conditions than under aerobic conditions. In conclusion, therefore, it can be said that in those with an increased intraocular pressure, regular, moderately intense aerobic exercise rather than short-lived intense exercise could be more useful.     

Exercise intensity and reduction in neurotic symptoms. A controlled follow-up study

The psychological benefits of walking and jogging were compared in 52 symptomatic neurotics over an 8-week training period and subsequent 6-month follow-up. Both groups showed marked reduction of anxiety, depression and global symptoms. Joggers had greater aerobic gain, but no greater psychologic benefit. Significantly larger numbers of joggers dropped out of the study. There was no relationship between aerobic gain and reduction of symptoms at the end of the program. However, at 6 months' follow-up, those with greater aerobic fitness had much lower anxiety levels. Changes in exercise frequency and aerobic capacity were also maintained at follow-up. Depression levels were not associated with aerobic fitness at follow-up. High initial exercise intensity appears to inhibit the forming of new exercise habits.     

Heart rate variability in smokers,sedentary and aerobically fit individuals

To test the hypothesis that certain lifestyles may affect cardiovascular regulatory mechanisms, heart rate variability (HRV) among three age-matched groups with different lifestyles (smoking, sedentary and aerobically fit) were compared. Heart rate variability was defined as the difference in heart rate during inhalation vs. exhalation. Heart rate was obtained from normal RR intervals, using a continuous electrocardiogram recording, while subjects were seated and breathing at an augmented tidal volume, and also while subjects were standing and breathing at normal tidal volumes. In the physically active group, heart rate variability was significantly elevated at rest as well as during some of the autonomic tests, when compared to the sedentary and smoker groups (p < 0.05). A hypothesis to explain this finding is that smoking or a sedentary lifestyle reduces vagal tone, whereas a physically active lifestyle, resulting in enhanced aerobic fitness, increases vagal tone. These findings may have cardiovascular health implications.     

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%).     

Double trouble (McArdle's disease and myasthenia gravis): How can exercise help?

We report a 29-year-old patient with McArdle's disease and myasthenia gravis. She had been debilitated with McArdle's disease since childhood (with marked rhabdomyolysis) and was obese. Myasthenia gravis was diagnosed at 24 years of age. After 3 months of aerobic exercise training, her exercise capacity increased significantly and she regained the ability to live independently. We conclude that even patients with profound neuromuscular diseases may benefit from carefully prescribed exercise training.     

Skeletal muscle mitochondrial dysfunction in alternating hemiplegia of childhood

Alternating hemiplegia of childhood is an uncommon disease characterized by repeated, transient attacks of hemiplegia. Its pathophysiology is uncertain, but attention recently has focused on possible mitochondrial abnormalities. Using ³¹P magnetic resonance spectroscopy, we studied gastrocnemius muscle in 5 patients with alternating hemiplegia, aged 8 to 30 (mean, 18) years, at rest and during incremental aerobic exercise and recovery. There were no significant differences in resting muscle between patients and a control group aged 7 to 42 (mean, 19) years. Exercise performance was grossly impaired in the patients, the mean duration being 30% of normal. The total change in pH during exercise was somewhat less than in control subjects, while the changes in phosphocreatine concentration and intracellular ADP were similar. Thus the average overall rate of fall of phosphocreatine concentration during exercise was three-fold greater than in control subjects. However, the initial rate of ATP turNovemberer at the start of exercise (a measure of muscle mass and efficiency) was not abnormal. During recovery, both the initial rate of phosphocreatine resynthesis and the calculated mitochondrial capacity were reduced by about 35%. This mitochondrial defect probably explains most of the abnormalities seen during exercise.