Spontaneous "second wind" and glucose-induced second "second wind" in McArdle disease: oxidative mechanisms

BACKGROUND: Blocked glycogen breakdown in McArdle disease impairs oxidative as well as anaerobic metabolism, but the contribution of impaired oxidative phosphorylation to everyday symptoms of McArdle disease remains poorly defined. OBJECTIVE: To evaluate the oxidative implications of the spontaneous second wind and variables that influence the development of this typical feature of McArdle disease. DESIGN: Assessment of exercise and oxidative capacity (.VO(2)) before and after the spontaneous "second wind" and with a glucose infusion after a spontaneous second wind. PATIENTS: Eight patients with complete myophosphorylase deficiency and 1 unique patient with 3% of normal myophosphorylase activity. MAIN OUTCOME MEASURES: Work capacity,.VO(2), heart rate, cardiac output. RESULTS: All patients with complete myophosphorylase deficiency (1) had low peak.VO(2) (mean +/- SD, 13.0 +/- 2.0 mL. kg(-1). min(-1)) in the first 6 to 8 minutes of exercise; (2) achieved a spontaneous second wind with increased exercise capacity between 8 and 12 minutes of exercise due to a more than 25% increase in peak.VO(2) (16.5 +/- 3.1 mL. kg(-1). min(-1)); and (3) with glucose infusion after a spontaneous second wind, experienced a further more than 20% increase in oxidative capacity (.VO(2), 19.9 +/- 3.9 mL. kg(-1). min(-1)). In the patient with residual myophosphorylase,.VO(2) (22.2 mL. kg(-1). min(-1)) in the first 6 to 8 minutes of exercise was approximately 2-fold higher than the mean of patients lacking myophosphorylase, and no significant improvement in exercise and oxidative capacity accompanied prolonged exercise or glucose infusion. CONCLUSIONS: First, the spontaneous second wind and the glucose-induced second second wind in McArdle disease are due to substrate-dependent increases in muscle oxidative capacity. Second, by providing glycogen-derived pyruvate, a small amount of residual myophosphorylase activity normalizes the oxidative deficit of complete myophosphorylase deficiency and virtually eliminates the spontaneous second wind and glucose-induced second second wind.     

Acute renal failure potentiates brain energy dysfunction elicited by methylmalonic acid

The influence of acute renal failure induced by gentamicin administration on the effects of MMA on mitochondrial respiratory chain complexes, citrate synthase, succinate dehydrogenase and creatine kinase activities in cerebral cortex and kidney of young rats were investigated. Animals received one intraperitoneal injection of saline or gentamicin (70 mg/kg). One hour after, the animals received three consecutive subcutaneous injections of MMA (1.67 μmol/g) or saline (11 h interval between injections) and 60 min after the last injection the animals were killed. Acute MMA administration decreased creatine kinase activity in both tissues and increased complexes I–III activity in cerebral cortex. Creatine kinase activity was also inhibited by gentamicin administration. Simultaneous administration of MMA and gentamicin increased the activities of citrate synthase in cerebral cortex and kidney and complexes II–III in cerebral cortex. The other enzyme activities in cerebral cortex and kidney of animals receiving MMA plus gentamicin did not significantly differ from those observed in animals receiving only MMA. Our present data is line with the hypothesis that MMA acts as a toxin in brain and kidney of rats and suggest that renal injury potentiates the toxicity of MMA on the Krebs cycle and respiratory chain in brain and peripheral tissues.     

Mitochondrial encephalomyopathy (focal cytochrome c oxidase deficiency) with transient episodes of muscle weakness and elevation of serum creatine kinase activity

A 17-year-old boy who had mitochondrial encephalomyopathy with focal deficiency of cytochrome c oxidase (CCO) activity is described. He experienced 3 episodes of muscle weakness, fatigability, nausea, vomiting and concomitant increase of serum creatine kinase activity, at the age of 13, 15 and 17 years. During interval there was no muscle weakness and the serum creatine kinase activity was within normal range. Increased levels of lactic acid and pyruvic acid were observed in the blood and cerebrospinal fluid. After an aerobic exercise test, lactic acid and pyruvic acid in the blood increased to an abnormally high level, and the arterial blood became acidic (pH 7.297). On EEG, occasional intermittent irregular theta activities were observed in the anterior region, but there were no abnormalities on CT and MRI in the central nervous system. In the biopsied muscle, ragged-red fibers comprised 20% on modified Gomori-trichrome staining and a number of fibers with no CCO activity were scattered throughout. The CCO activity in the mitochondria isolated from the biopsied muscle was reduced to 49.2 nmol/min/mg protein (normal range 144.7-355.8), while other mitochondrial enzyme activities in the electron transport system were normal. From these data, the patient was considered to have a unique form of mitochondrial encephalomyopathy. By the administration of a large amount of coenzyme Q10, episodes of muscle weakness and nausea, and an increase of lactic acid and pyruvic acid in the blood after aerobic exercise test were no longer observed.     

Exercise capacity in a child with McArdle disease

We report the exercise capacity of an 8-year-old boy with clinical, histological, biochemical, and genetic evidence of McArdle disease. The patient presented with severe myalgia, proteinuria, hematuria, pyrexia, and elevated creatine kinase after swimming. After pre-exercise ingestion of sucrose, he performed treadmill exercise to symptom limitation. His peak oxygen uptake (18.8 mL/kg/min) and ventilatory threshold (16.0 mL/kg/min) were reduced by 40% and 20% compared with healthy age-matched and gender-matched controls. The results suggest that exercise capacity is reduced early in life in patients with McArdle disease and suggest the need for prophylactic exercise training (following pre-exercise feeding to prevent rhabdomyolysis) to minimize deconditioning.     

耐力训练模型大鼠骨骼肌代谢酶与自由基变化

背景：骨骼肌代谢酶与自由基的变化与不同的运动方式和运动强度有关。 目的：观察递增大强度耐力训练下大鼠骨骼肌代谢酶活性和自由基代谢的变化。 方法：健康雄性SD大鼠,随机分为安静组和运动组,后者建立8周的递增大强度耐力训练模型,训练结束后取骨骼肌样本测试肌酸激酶、乳酸脱氢酶、谷草转氨酶、谷丙转氨酶、丙二醛、总抗氧化酶、过氧化氢酶水平。 结果与结论：8周训练后,运动组大鼠肌酸激酶、乳酸脱氢酶、谷草转氨酶、谷丙转氨酶酶活性及丙二醛水平均高于安静组(P < 0.01或0.05),而总抗氧化酶、过氧化氢酶、谷胱甘肽过氧化物酶活性低于安静组(P < 0.05)。说明8周的递增大强度的耐力训练能使骨骼肌受到一定的损伤,并且提示抗氧化酶活性的下降和部分代谢酶活性以升高之间有一定的关系。     

Tianeptine treatment induces antidepressive-like effects and alters BDNF and energy metabolism in the brain of rats

The present study was aimed at investigating the behavioral and molecular effects of tianeptine. To this aim, Wistar rats were treated with tianeptine (5, 10 and 15 mg/kg) or imipramine (30 mg/kg) acutely and chronically. The results showed that both treatments reduced the immobility time. The BDNF levels were increased in the prefrontal cortex with tianeptine and decreased in the nucleus accumbens after acute treatment; in chronic treatment, BDNF levels were increased in the prefrontal and hippocampus with tianeptine. Acute treatment decreased the citrate synthase activity in the prefrontal cortex with tianeptine, and increased it in the amygdala with imipramine; chronic treatment increased the citrate synthase in the hippocampus with tianeptine. The creatine kinase was increased in the prefrontal cortex with tianeptine and in the amygdala with imipramine after acute treatment; chronic treatment increased the creatine kinase activity in the hippocampus with imipramine and tianeptine. The complex I activity was decreased in the prefrontal cortex with imipramine and increased in the hippocampus with tianeptine. The other complexes were increased with imipramine and tianeptine at all doses, but were related to the treatment given and the brain area studied. Chronic treatment increased the malate dehydrogenase activity in the amygdala with tianeptine. Acute treatment decreased the succinate activity in the prefrontal cortex, hippocampus and amygdala with tianeptine; chronic treatment increased the succinate activity in the hippocampus with tianeptine at all doses. In conclusion, tianeptine exerted antidepressant-like behavior which can be attributed to its effects on pathways related to depression, such as BDNF and metabolism energy.     

Aerobic training in patients with anoctamin 5 myopathy and hyperckemia

Introduction: Anoctamin 5 deficiency has recently been defined to cause limb‐girdle muscular dystrophy type 2L (LGMD2L) with pronounced hyperCKemia. No treatment interventions have been made so far in this condition. Methods: In 6 patients with LGMD2L, we studied the effect of home‐based, pulse‐watch monitored, moderate‐intensity exercise on a cycle ergometer for 30 minutes, 3 times weekly, for 10 weeks. Plasma creatine kinase (CK) was assessed before, during, and after the program as a marker of muscle damage. Primary outcome measures were maximum oxygen uptake (VO_2max) and time in the 5‐repetitions‐sit‐to‐stand test (FRSTST). Results: Training resulted in improvements in VO_2max (27 ± 7%; P = 0.0001) and FRSTST time (35 ± 12%; P = 0.007). Improvements in physiologic and functional muscle testing were accompanied by stable CK levels and no reports of adverse effects. Conclusions: These findings suggest that supervised aerobic exercise training is safe and effective in improving oxidative capacity and muscle function in patients with anoctamin 5 deficiency. Muscle Nerve 50 : 119–123, 2014     

Endurance training: an effective and safe treatment for patients with LGMD2I

We studied the effect of aerobic training on conditioning in patients with limb-girdle muscular dystrophy type 2I (LGMD2I). Nine patients with LGMD2I cycled fifty 30-minute sessions at 65% of their maximal oxygen uptake over 12 weeks. Training significantly improved work capacity, paralleled by self-reported improvements. Creatine kinase levels did not increase significantly, and muscle morphology was unaffected. Moderate-intensity endurance training is a safe method to increase exercise performance and daily function in patients with LGMD2I.     

Lactate dehydrogenase isoenzyme in detecting carriers of Duchenne muscular dystrophy

Thirty mothers of patients with Duchenne muscular dystrophy were studied with serum enzyme tests, including serum glutamic-oxaloacetic transminase, creatine kinase, and lactate dehydrogenase isoenzymes. In addition, females from the mothers' pedigrees were studied. Lactate dehydrogenase isoenzyme 5 determinations were as senitive an indicator of carrier status as creatine kinase and also identified several mothers who had normal dehydrogenase isoenzyme 5 determinations, as well as extensive pedigree testing, identified 28 to 30 mothers as probable heterozygotes. These data independently support the suggestion that cases of Duchenne muscular dystrophy as a result of spontaneous mutation are more uncommon than currently accepted.     

复方中药对小鼠运动能力及其生化指标影响的比较

背景：有关中药对动物运动能力的实验研究较多，能够真正体现出复方中药对提高运动员机体运动能力的研究并不多，尤其缺乏对复方中药进行对比的研究。 目的：观察不同复方中药制剂对小鼠运动能力的影响，筛选作用明确的复方制剂。 方法：8周龄纯系雄性昆明种小鼠80只随机数字表法分成8组，每组10只：对照组、复方一~七组，各组动物体质量差异无显著性意义。复方一的主要成分是血竭、麝香，复方二的主要成分为秦归、白术、白芍，复方三的主要成分为白术、白芷、三七，复方四的主要成分为白芷、乳香、当归和甘草，复方五的主要成分为归尾，复方六的主要成分为川红花、丹参，复方七的主要成为当归、麝香等，其中复方一~五为验方，复方六为训练队常用经验药物，复方七为中医配置药方。复方一~七组灌喂相应中药复方1.17，0.78，0.78，1.17，7.02，5.53，11.70 g/(kg•d)，4周。对照组灌胃给予生理盐水。灌胃给药第4~6天进行20 min/d无负重的适应性游泳训练3 d，休息1 d后每周进行6 d的游泳训练，强度由30 min/d逐渐递增，递增率为10 min/d，持续2 h，然后进行负重游泳，由小鼠自身体质量2%进行负重游泳，每天以1%的递增率逐渐增加负荷直到实验结束。在整个实验过程中，每周安排一次大强度的游泳训练，使各小鼠达到力竭状态。观察小鼠训练情况以及中药干预4周后血清肌酸激酶和乳酸脱氢酶的变化。 结果与结论：80只小鼠均进入结果分析。各复方药物对小鼠体质量影响不明显，复方二和复方六药物组小鼠的力竭时间最长。各中药复方对小鼠运动后血清肌酸激酶活性均有一定的抑制作用，但以复方六和复方二效果较好(P < 0.05)。与对照组比较，各复方组小鼠血清乳酸脱氢酶活性均下降，但仅与复方二、六组差异有显著性意义(P < 0.05)。提示复方药物二和复方药物六能显著提高小鼠的运动能力，延迟运动机体骨骼肌维系的损伤，其机制可能与复方药物中所含的主要成分当归、川红花、丹参等有密切关系。     

Inhibition of energy metabolism in cerebral cortex of young rats by the medium-chain fatty acids accumulating in MCAD deficiency

Patients affected by medium-chain acyl CoA dehydrogenase (MCAD) deficiency, a frequent inborn error of metabolism, suffer from acute episodes of encephalopathy. However, the mechanisms underlying the neuropathology of this disease are poorly known. In the present study, we investigated the in vitro effect of the medium-chain fatty acids (MCFA), at concentrations varying from 0.01 to 3 mM, accumulating in MCAD deficiency on some parameters of energy metabolism in cerebral cortex of young rats. (14)CO(2) production from [U(14)] glucose, [1-(14)C] acetate and [1,5-(14)C] citrate was evaluated by incubating cerebral cortex homogenates from 30-day-old rats in the absence (controls) or presence of octanoic acid, decanoic acid or cis-4-decenoic acid. OA and DA significantly reduced (14)CO(2) production from acetate by around 30-40%, and from glucose by around 70%. DA significantly reduced (14)CO(2) production from citrate by around 40%, while OA did not affect this parameter. cDA inhibited (14)CO(2) production from all tested substrates by around 30-40%. The activities of the respiratory chain complexes and of creatine kinase were also tested in the presence of DA and cDA. Both metabolites significantly inhibited cytochrome c oxidase activity (by 30%) and complex II-III activity (DA, 25%; cDA, 80%). Furthermore, only cDA inhibited complex II activity (by 30%), while complex I-III and citrate synthase were not affected by these MCFA. On the other hand, only cDA reduced the activity of creatine kinase in total homogenates, as well as in mitochondrial and cytosolic fractions from cerebral cortex (by 50%). The data suggest that the major metabolites which accumulate in MCAD deficiency, with particular emphasis to cDA, compromise brain energy metabolism. We presume that these findings may contribute to the understanding of the pathophysiology of the neurological dysfunction of MCAD deficient patients.     

Aerobic training in patients with myotonic dystrophy type 1

The effect of 12 weeks of aerobic training on a cycle ergometer was studied in 12 patients with myotonic dystrophy. Efficacy was evaluated by cycle testing and muscle morphology before and after training. Patients increased their maximal oxygen uptake by 14%, the maximal workload by 11%, muscle fiber diameter increased significantly, and creatine kinase did not increase with training. The study indicates that aerobic training is safe and can improve fitness effectively in patients with myotonic dystrophy.     

One-legged bicycling as an assessment tool for patients with stroke

OBJECTIVE: To assess whether one-legged bicycling correlates with muscle strength and thereby could work as an outcome measure for persons with stroke. METHODS: The study comprised 29 men (age 35-65) with a first occurrence of stroke 6-35 months earlier. Each leg was evaluated separately. A ramp protocol was used (10 W/min), with continuous recording of the ventilatory uptake (Vo(2)) and heart rate. An isokinetic dynamometer was used to assess strength and endurance. Enzyme assays were performed on muscle biopsy samples. RESULTS: The peak isometric strength and isokinetic strength of the paretic leg correlated with the max. W on the bicycle. The oxidative enzyme citrate synthase correlated with the workload for both legs on the bicycle and lactate dehydrogenase correlated with peak isometric strength in both legs. CONCLUSIONS: The one-legged bicycle exercise test can be used to assess endurance in persons with a previous stroke as it correlates with dynamometer testing and muscle biopsies.     

The effect of aerobic exercise on serum creatine kinase activities

Aerobic exercise is now a common form of recreational exercise among young women. In a previous study, more than a third of a group of young mothers volunteering blood samples to establish a creatine kinase (CK) reference range for Duchenne muscular dystrophy (DMD) carrier detection regularly participated in aerobic exercise programs. Aerobic exercise programs include eccentric exercises. As eccentric exercise is known to produce a delayed CK peak, this study was carried out to determine the effect of aerobic exercise on serum CK activities. The postexercise serum CK activity peak was monitored in 15 young women (age range 20-23 years) following aerobic exercise classes (45 minutes on 3 consecutive days). Peak values at 24-48 hours following the last class ranged from 90 to 3473 U/liter, or 1.55 to 34.71 times resting values. It is concluded that aerobic exercise programs should be excluded in order to obtain accurate resting serum CK values for muscle disease diagnosis.     

Chronic ketosis and cerebral metabolism

The effects of chronic ketosis on cerebral metabolism were determined in adult rats maintained on a high-fat diet for approximately three weeks and compared to a control group of animals. The fat-fed rats had statistically significantly lower blood glucose concentrations and higher blood beta-hydroxybutyrate and acetoacetate concentrations; higher brain concentrations of bound glucose, glucose 6-phosphate, pyruvate, lactate, beta-hydroxybutyrate, citrate, alpha-ketoglutarate, alanine, and adenosine triphosphate (ATP); lower brain concentrations of fructose 1,6-diphosphate, aspartate, adenosine diphosphate (ADP), creatine, cyclic nucleotides, succinyl coenzyme A (CoA), acid-insoluble CoA, and total CoA; and similar brain concentrations of glucose, malate, calculated oxaloacetate, glutamate, glutamine, adenosine monophosphate, phosphocreatine, reduced CoA, acetyl CoA, sodium, potassium, chloride, and water content. The metabolite data in the chronically ketotic rats demonstrate an increase in the cerebral energy reserve and energy charge. These data also suggest negative modification of the enzymes phosphofructokinase, pyruvic dehydrogenase, and alpha-ketoglutaric dehydrogenase; positive modification of glycogen synthase; and possible augmentation of the hexose transport system. There was no demonstrable difference in brain pH, water content, or electrolytes in the two groups of animals. We speculate that the increased brain ATP/ADP ratio is central to most, if not all, the observed metabolic perturbations and may account for the increased neuronal stability that accompanies chronic ketosis.     

A study on the serum biochemistry in carrier detection of Duchenne muscular dystrophy

The serum levels of creatine kinase, creatine kinase isoenzyme (MB), lactate dehydrogenase, pyruvate kinase and myoglobin were studied in 85 carriers of Duchenne muscular dystrophy and 125 normal female controls. The results showed that the best single test for carrier detection was myoglobin or creatine kinase, the combination of multiple tests could increase the effectiveness of carrier detection, in which the best and most rational tests to use in combination were creatine kinase, lactate dehydrogenase and myoglobin.     

Exercise Reveals the Interrelation of Physical Fitness,Inflammatory Response,Psychopathology, and Autonomic Function in Patients With Schizophrenia

Maintaining and improving fitness are associated with a lower risk of premature death from cardiovascular disease. Patients with schizophrenia are known to exercise less and have poorer health behaviors than average. Physical fitness and physiological regulation during exercise tasks have not been investigated to date among patients with schizophrenia. We studied autonomic modulation in a stepwise exhaustion protocol in 23 patients with schizophrenia and in matched controls, using spirometry and lactate diagnostics. Parameters of physical capacity were determined at the aerobic, anaerobic, and vagal thresholds (VT), as well as for peak output. VT was correlated with psychopathology, as assessed by the Positive and Negative Syndrome Scale, with the inflammatory markers IL-1β, IL-6, and TNF-α and with peak output. The MANOVA for heart and breathing rates, as well as for vagal modulation and complexity behavior of heart rate, indicated a profound lack of vagal modulation at all intensity levels, even after the covariate carbon monoxide concentration was introduced as a measure of smoking behavior. Significantly decreased physical capacity was demonstrated at the aerobic, anaerobic, and VT in patients. After the exercise task, reduced vagal modulation in patients correlated negatively with positive symptoms and with levels of IL-6 and TNF-α. This study shows decreased physical capacity in patients with schizophrenia. Upcoming intervention studies need to take into account the autonomic imbalance, which might predispose patients to arrhythmias during exercise. Results of inflammatory parameters are suggestive of a reduced activity of the anti-inflammatory cholinergic pathway in patients, leading to a pro-inflammatory state.Key words: heart rate, physical exercise, respiration, schizophrenia, vagal threshold, cardiac death, inflammation, physical fitness     

Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial

OBJECTIVE: To determine whether treatment with creatine can improve exercise intolerance in myophosphorylase deficiency (McArdle disease). DESIGN: Double-blind, placebo-controlled crossover study with oral creatine monohydrate supplementation. PATIENTS: Nine patients with biochemically and genetically proven McArdle disease were treated. INTERVENTION: Five days of daily high-dose creatine intake (150 mg/kg body weight) were followed by daily low-dose creatine intake (60 mg/kg). Each treatment phase with creatine or placebo lasted 5 weeks. MAIN OUTCOME MEASURES: The effect of treatment was estimated at the end of each treatment phase by recording clinical scores, ergometer exercise test results, phosphorus 31 nuclear magnetic resonance spectroscopy, and surface electromyography. RESULTS: Of 9 patients, 5 reported improvement of muscle complaints with creatine. Force-time integrals (P =.03) and depletion of phosphocreatine (P =.04) increased significantly during ischemic exercise with creatine. Phosphocreatine depletion also increased significantly during aerobic exercise (P =.006). The decrease of median frequency in surface electromyograms during contraction was significantly larger (P =.03) with creatine. CONCLUSION: This is the first controlled study indicating that creatine supplementation improves skeletal muscle function in McArdle disease.     

Riboflavin responsive multiple acyl-CoA dehydrogenase deficiency: functional evaluation of recovery after high dose vitamin supplementation.

The effect of riboflavin supplementation on muscle performance and exercise metabolism was investigated in four patients with multiple acyl-coenzyme A dehydrogenase deficiency (MAD). Maximum oxygen consumption and endurance measurements were performed to assess the patients' aerobic capacity and energy metabolism during exercise. They were tested before and after treatment with pharmacological doses of riboflavin. The initially low maximum oxygen consumption and high levels of blood lactate during submaximal exercise suggest that the oxidation of both fatty acids and carbohydrates was severely impaired. All four patients experienced a dramatic improvement in aerobic performance under riboflavin supplementation.