Fat metabolism during exercise in patients with McArdle disease.

OBJECTIVE: It is known that muscle phosphorylase deficiency restricts carbohydrate utilization, but the implications for muscle fat metabolism have not been studied. We questioned whether patients with McArdle disease can compensate for the blocked muscle glycogen breakdown by enhancing fat oxidation during exercise. METHODS: We studied total fat oxidation by indirect calorimetry and palmitate turnover by stable isotope methodology in 11 patients with McArdle disease and 11 healthy controls. Cycle exercise at a constant workload of 50% to 60% of maximal oxygen uptake capacity was used to evaluate fatty acid oxidation (FAO) in the patients. Healthy controls were exercised at the same absolute workload. RESULTS: We found that palmitate oxidation and disposal, total fat oxidation, and plasma levels of palmitate and total free fatty acids (FFAs) were significantly higher, whereas total carbohydrate oxidation was lower, during exercise in patients with McArdle disease vs healthy controls. We found augmented fat oxidation with the onset of a second wind, but further increases in FFA availability, as exercise continued, did not result in further increases in FAO. CONCLUSION: These results indicate that patients with McArdle disease have exaggerated fat oxidation during prolonged, low-intensity exercise and that increased fat oxidation may be an important mechanism of the spontaneous second wind. The fact that increasing availability of free fatty acids with more prolonged exercise did not increase fatty acid oxidation suggests that blocked glycogenolysis may limit the capacity of fat oxidation to compensate for the energy deficit in McArdle disease.

The exercise metaboreflex is maintained in the absence of muscle acidosis: insights from muscle microdialysis in humans with McArdle's disease.

1. In McArdle's disease, muscle glycogenolysis is blocked, which results in absent lactate and enhanced ammonia production in working muscle. Using McArdle patients as an experimental model, we studied whether lactate and ammonia could be mediators of the exercise pressor reflex. 2. Changes in muscle interstitial ammonia and lactate were compared with changes in blood pressure and muscle sympathetic nerve activity (MSNA) during static arm flexor exercise at 30% of maximal contraction force. Muscle interstitial changes in lactate and ammonia were assessed by microdialysis of the biceps muscle, and MSNA by peroneal nerve microneurography, in six McArdle patients and 11 healthy, matched controls. One McArdle patient also had myoadenylate deaminase deficiency, a condition associated with abolished ammonia production in exercise. 3. Exercise-induced increases were higher in McArdle patients vs. controls for MSNA (change of 164 +/- 71 vs. 59 +/- 19%) and blood pressure (change of 47 +/- 7 vs. 38 +/- 4 mmHg). Interstitial lactate increased in controls (peak change 1.3 +/- 0.2 mmol x l(-1)) and decreased in McArdle patients (peak change -0.5 +/- 0.1 mmol x l(-1)) during and after exercise. Interstitial ammonia did not change during exercise in either group, but was higher post-exercise in McArdle patients, except in the patient with myoadenylate deaminase deficiency who had a flat ammonia response. This patient had an increase in MSNA and blood pressure comparable to other patients. MSNA and blood pressure responses were maintained during post-exercise ischaemia in both groups, indicating that sympathetic activation was caused, at least partly, by a metaboreflex. 4. In conclusion, changes in muscle interstitial lactate and ammonia concentrations during and after exercise are temporally dissociated from changes in MSNA and blood pressure in both patients with McArdle's disease and healthy control subjects. This suggests that muscle acidification and changes in interstitial ammonia concentration are not mediators of sympathetic activation during exercise.

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.

Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA.

OBJECTIVE: To elucidate the molecular basis of a mitochondrial myopathy associated with recurrent myoglobinuria and cytochrome c oxidase (COX) deficiency in muscle. BACKGROUND: Recurrent myoglobinuria is typically seen in patients with inborn errors of carbohydrate or lipid metabolism, the main sources of energy for muscle contraction. Relatively little attention has been directed to defects of the mitochondrial respiratory chain in patients with otherwise unexplained recurrent myoglobinuria. METHODS: Having documented COX deficiency histochemically and biochemically in the muscle biopsy from a patient with exercise-induced recurrent myoglobinuria, the authors sequenced the three mitochondrial DNA (mtDNA)-encoded COX genes, and performed restriction fragment length polymorphism analysis and single-fiber PCR. RESULTS: The authors identified a nonsense mutation (G5920A) in the COX I gene in muscle mtDNA. The mutation was heteroplasmic and abundantly present in COX-negative fibers, but less abundant or absent in COX-positive fibers; it was not found in blood or fibroblasts from the patient or in blood samples from the patient's asymptomatic mother and sister. CONCLUSIONS: The G5920A mutation caused COX deficiency in muscle, explaining the exercise intolerance and the low muscle capacity for oxidative phosphorylation documented by cycle ergometry. The sporadic occurrence of this mutation in muscle alone suggests that it arose de novo in myogenic stem cells after germ-layer differentiation. Mutations in mtDNA-encoded COX genes should be considered in patients with recurrent myoglobinuria.

McArdle's disease presenting with asymmetric, late-onset arm weakness.

McArdle's disease or myophosphorylase deficiency is one of the most common muscle glycogenoses and typically presents in childhood or adolescence with exercise intolerance, myalgia, myoglobinuria, and cramps in exercising muscle. We describe an elderly man who developed asymmetric proximal arm weakness at age 73. He had no history of exercise-induced cramps, myalgias, or myoglobinuria. Creatine kinase levels were elevated, serum lactate did not rise on ischemic exercise testing, and muscle biopsy showed a vacuolar myopathy with absent myophosphorylase activity. This unusual case demonstrates that McArdle's disease may present with fixed, asymmetric proximal weakness at an advanced age and should be considered in this clinical setting, especially when a history of poor exercise tolerance can be elicited.

A modular NIRS system for clinical measurement of impaired skeletal muscle oxygenation.

Near-infrared spectrometry (NIRS) is a well-known method used to measure in vivo tissue oxygenation and hemodynamics. This method is used to derive relative measures of hemoglobin (Hb) + myoglobin (Mb) oxygenation and total Hb (tHb) accumulation from measurements of optical attenuation at discrete wavelengths. We present the design and validation of a new NIRS oxygenation analyzer for the measurement of muscle oxygenation kinetics. This design optimizes optical sensitivity and detector wavelength flexibility while minimizing component and construction costs. Using in vitro validations, we demonstrate 1) general optical linearity, 2) system stability, and 3) measurement accuracy for isolated Hb. Using in vivo validations, we demonstrate 1) expected oxygenation changes during ischemia and reactive hyperemia, 2) expected oxygenation changes during muscle exercise, 3) a close correlation between changes in oxyhemoglobin and oxymyoglobin and changes in deoxyhemoglobin and deoxymyoglobin and limb volume by venous occlusion plethysmography, and 4) a minimal contribution from movement artifact on the detected signals. We also demonstrate the ability of this system to detect abnormal patterns of tissue oxygenation in a well-characterized patient with a deficiency of skeletal muscle coenzyme Q(10). We conclude that this is a valid system design for the precise, accurate, and sensitive detection of changes in bulk skeletal muscle oxygenation, can be constructed economically, and can be used diagnostically in patients with disorders of skeletal muscle energy metabolism.

Muscle phosphoglycerate mutase deficiency with tubular aggregates: effect of dantrolene.

A patient with muscle phosphoglycerate mutase deficiency (PGAMD) and exercise-induced muscle cramps had tubular aggregates in muscle and increased muscle Ca2+-adenosine triphosphatase and calcium content. Two ischemic forearm exercise tests induced contractures in the patient. On dantrolene treatment, the patient became asymptomatic, and the ischemic test was performed without contracture. These findings suggest that cramps in muscle PGAMD are caused by a high calcium release from the sarcoplasmic reticulum relative to calcium re-uptake capacity.

Oral branched-chain amino acids do not improve exercise capacity in McArdle disease.

To determine whether oral branched-chain amino acids (BCAAs) improve exercise capacity, six fasting patients with McArdle's disease were given a solution of BCAA (77 mg/kg) or a control noncaloric beverage 30 minutes before exercise. The BCAA meal tripled plasma BCAA levels, increased BCAA catabolism as indicated by greater exercise increases in plasma glutamine and alanine, but lowered mean peak free fatty acid levels and reduced exercise capacity in five of six patients. Lower work capacity may be attributed to a net reduction in muscle fuel availability after BCAA administration.

Submaximal delayed-onset muscle soreness: correlations between MR imaging findings and clinical measures.

PURPOSE: To assess correlations between muscle edema on magnetic resonance (MR) images and clinical indexes of muscle injury in delayed-onset muscle soreness (DOMS) produced by submaximal exercise protocols. MATERIALS AND METHODS: Sixteen subjects performed 36 elbow flexions ("biceps curls") at one of two submaximal workloads that emphasized eccentric contractions. Changes in MR imaging findings, plasma levels of creatine kinase, and pain scores were correlated. RESULTS: Both exercise protocols produced DOMS in all subjects. The best correlation was between change in creatine kinase level and volume of muscle edema on MR images, regardless of the workload. Correlations tended to be better with the easier exercise protocol. CONCLUSION: Whereas many previous studies of DOMS focused on intense exercise protocols to ensure positive results, the present investigation showed that submaximal workloads are adequate to produce DOMS and that correlations between conventionally measured indexes of injury may be enhanced at lighter exercise intensities.

Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies.

Muscle acidosis has been implicated as a major determinant of reflex sympathetic activation during exercise. To test this hypothesis we studied sympathetic exercise responses in metabolic myopathies in which muscle acidosis is impaired or augmented during exercise. As an index of reflex sympathetic activation to muscle, microneurographic measurements of muscle sympathetic nerve activity (MSNA) were obtained from the peroneal nerve. MSNA was measured during static handgrip exercise at 30% of maximal voluntary contraction force to exhaustion in patients in whom exercise-induced muscle acidosis is absent (seven myophosphorylase deficient patients; MD [McArdle's disease], and one patient with muscle phosphofructokinase deficiency [PFKD]), augmented (one patient with mitochondrial myopathy [MM]), or normal (five healthy controls). Muscle pH was monitored by 31P-magnetic resonance spectroscopy during handgrip exercise in the five control subjects, four MD patients, and the MM and PFKD patients. With handgrip to exhaustion, the increase in MSNA over baseline (bursts per minute [bpm] and total activity [%]) was not impaired in patients with MD (17+/-2 bpm, 124+/-42%) or PFKD (65 bpm, 307%), and was not enhanced in the MM patient (24 bpm, 131%) compared with controls (17+/-4 bpm, 115+/-17%). Post-handgrip ischemia studied in one McArdle patient, caused sustained elevation of MSNA above basal suggesting a chemoreflex activation of MSNA. Handgrip exercise elicited an enhanced drop in muscle pH of 0.51 U in the MM patient compared with the decrease in controls of 0.13+/-0.02 U. In contrast, muscle pH increased with exercise in MD by 0.12+/-0.05 U and in PFKD by 0.01 U. In conclusion, patients with glycogenolytic, glycolytic, and oxidative phosphorylation defects show normal muscle sympathetic nerve responses to static exercise. These findings indicate that muscle acidosis is not a prerequisite for sympathetic activation in exercise.

Reduced levels of skeletal muscle Na+K+ -ATPase in McArdle disease.

We evaluated the hypothesis that impaired sarcolemmal function associated with exaggerated potassium release, impaired potassium uptake, or both may contribute to exertional fatigue and abnormal circulatory responses to exercise in McArdle disease (MD). The cellular mechanism of exertional fatigue and muscle injury in MD is unknown but likely involves impaired function of the ATPases that couple ATP hydrolysis to cellular work, including the muscle sodium potassium pump (Na+K+-ATPase). However, the concentration of muscle Na+K+ pumps in MD is not known, and no studies have related exercise increases in blood potassium concentrations to muscle Na+K+ pump levels. We measured muscle Na+K+ pumps (3H-ouabain binding) and plasma K+ in response to 20 minutes of cycle exercise in six patients with MD and in six sex-, age-, and weight-matched sedentary individuals. MD patients had lower levels of 3H-ouabain binding (231 +/- 18 pmol/g w.w., mean +/- SD, range, 210 to 251) than control subjects (317 +/- 37, range, 266 to 371, p < 0.0004), higher peak increases in plasma potassium in response to 45 +/- 7 W cycle exercise (MD, 1.00 +/- 0.15 mmol/L; control subjects, 0.48 +/- 0.09; p < 0.0001), and mean exercise heart rate responses to exercise that were 45 +/- 12 bpm greater than control subjects. Our results indicate that Na+K+ pump levels are low in MD patients compared with healthy subjects and identify a limitation of potassium reuptake that could result in sarcolemmal failure during peak rates of membrane activation and may promote exaggerated potassium-activated circulatory responses to submaximal exercise. The mechanism of the low Na+K+ pump concentrations in MD is unknown but may relate to deconditioning or to disruption of a close functional relationship between membrane ion transport and glycolysis.

Mitochondrial encephalomyopathy with coenzyme Q10 deficiency.

Coenzyme Q10 (CoQ10) transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There is one published report of human CoQ10 deficiency describing two sisters with encephalopathy, proximal weakness, myoglobinuria, and lactic acidosis. We report a patient who had delayed motor milestones, proximal weakness, premature exertional fatigue, and episodes of exercise-induced pigmenturia. She also developed partial-complex seizures. Serum creatine kinase was approximately four times the upper limit of normal and venous lactate was mildly elevated. Skeletal muscle biopsy revealed many ragged-red fibers, cytochrome c oxidase-deficient fibers, and excess lipid. In isolated muscle mitochondria, impaired oxygen consumption was corrected by the addition of decylubiquinone. During standardized exercise, ventilatory and circulatory responses were compatible with a defect of oxidation-phosphorylation, which was confirmed by near-infrared spectroscopy analysis. Biochemical analysis of muscle extracts revealed decreased activities of complexes I+II and I+III, while CoQ10 concentration was less than 25% of normal. With a brief course of CoQ10 (150 mg daily), the patient reported subjective improvement. The triad of CNS involvement, recurrent myoglobinuria, and ragged-red fibers should alert clinicians to the possibility of CoQ10 deficiency.

Exercise fuel mobilization in mitochondrial myopathy: a metabolic dilemma.

In mitochondrial myopathy, severely impaired muscle oxidative capacity poses a dilemma for metabolic regulation in exercise. We inquired whether fuel mobilization during exercise in mitochondrial myopathy is adjusted to the reduced capacity to oxidize substrate, or if fuel is mobilized in excess of oxidative capacity. Hormonal and metabolic responses to 20 minutes of cycle exercise were studied in 4 patients with mitochondrial myopathy working at near maximal effort and in 4 healthy matched controls. On 2 separate days, controls were studied at the same absolute (A) workload (9 +/- 3 W) and the same relative (R) workload (77 +/- 9 W) as performed by the patients. During exercise, average glucose production was higher in patients (28 +/- 5 micromol min(-1) kg(-1)) than in controls at both workloads (A, 12 +/- 1; R, 18 +/- 2 micromol min(-1) kg(-1)). Exercise-induced increases in plasma glucose, growth hormone, epinephrine, norepinephrine, corticotropin, and lactate, and decreases in plasma insulin and pH were also larger in patients compared with findings in controls at both workloads. In conclusion, mitochondrial myopathies are associated with excessive neuroendocrine responses and mobilization of glucose during exercise. These responses augment ATP synthesis but result in progressive accumulation of nonoxidized substrates. Apparently, substrate mobilization and neuroendocrine responses in exercise are linked to oxidative demand rather than to oxidative capacity in working muscle.

Paradoxically enhanced glucose production during exercise in humans with blocked glycolysis caused by muscle phosphofructokinase deficiency.

Muscle phosphofructokinase deficiency (PFKD) is characterized by exercise intolerance due to the enzymatic block in muscle glycolysis. Glucose infusion increases exertional fatigue in these patients, probably by decreasing the availability of free fatty acids (FFA) and ketones, which play a crucial role in ATP production during exercise in PFKD. This suggests that a lower than normal hepatic glucose production would be appropriate during exercise in PFKD. To investigate glucoregulation in PFKD, we measured glucose turnover and hormonal and metabolic responses to 20 minutes of cycle exercise at near maximal effort in three patients with PFKD and in healthy matched controls studied at the same absolute (A, 15 to 30 Watts) and relative (R, 35 to 80 Watts, matched heart rates) work load as the patients. During exercise, mean glucose production was higher in all patients versus controls (30 +/- 4 versus A: 18 +/- 2 and R: 20 +/- 1 mumol.min-1.kg-1). Mean glucose utilization during exercise was similar in patients and controls working at the same relative work load and higher than in controls at the low work load. Exercise-induced increases in arterialized blood were higher in all patients for glucose, FFA, growth hormone, glucagon, and norepinephrine. Plasma alanine and lactate always decreased during exercise in patients and consistently increased in controls. In conclusion, an enhanced neuroendocrine response and a paradoxically exaggerated mobilization of glucose occurs during exercise in PFKD. The responses are probably initiated by neural feedback elicited by disturbances in local muscle metabolism. The responses promote delivery of oxidizable fat to muscle, but at the expense of accumulation and futile cycling of glucose.

Tricarboxylic acid cycle intermediates during incremental exercise in healthy subjects and in patients with McArdle's disease.

1. The importance of the level of tricarboxylic acid cycle intermediates (malate, citrate and fumarate) for energy transduction during exercise has been investigated in six healthy subjects and in two patients with muscle phosphorylase deficiency (McArdle's disease). 2. Healthy subjects cycled for 10 min at low (50 W), moderate [130 +/- 6 W (mean +/- SEM)] and high (226 +/- 12 W) work rates, corresponding to 26, 50 and 80% of their maximal O2 uptake, respectively. Patients with McArdle's disease cycled for 11-13 min at submaximal (40 W) rates, and to fatigue at maximal work rates of 60-90 W. 3. In healthy subjects, phosphocreatine was unchanged during low work rates, but decreased to 79 and 32% of the initial level during moderate and high work rates. In patients with McArdle's disease, phosphocreatine decreased to 82 and 34% of the initial level during submaximal and peak exercise. Muscle lactate increased in healthy subjects during exercise at moderate and high work rates, but remained low in patients with McArdle's disease. 4. In healthy subjects, tricarboxylic acid cycle intermediates were similar at rest and at low work rates (0.48 +/- 0.04 mmol/kg dry weight), but increased to 1.6 +/- 0.2 mmol/kg dry weight and 4.0 +/- 0.3 mmol/kg dry weight at moderate and high work rates. The tricarboxylic acid cycle intermediate level in patients with McArdle's disease was similar to that in healthy subjects at rest, but was markedly reduced during exercise when compared at the same relative intensity. The peak level of tricarboxylic acid cycle intermediates in patients with McArdle's disease was 22% of that in healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic myopathies.

Metabolic myopathies are disorders of muscle energy production that result in skeletal muscle dysfunction. Cardiac and systemic metabolic dysfunction may coexist. Symptoms are often intermittent and provoked by exercise or changes in supply of lipid and carbohydrate fuels. Specific disorders of lipid and carbohydrate metabolism in muscle are reviewed. Evaluation often requires provocative exercise testing. These tests may include ischemic forearm exercise, aerobic cycle exercise, and 31P magnetic resonance spectroscopy with exercise.

Molecular genetic studies of muscle lactate dehydrogenase deficiency in white patients.

We identified two new mutations in 2 white patients with muscle lactate dehydrogenase deficiency. Both patients had exercise intolerance, cramps, and recurrent myoglobinuria. One patient was homozygous for a 2-bp deletion in exon 5, resulting in a frameshift with premature termination of translation. The second patient was homozygous for a G-->A substitution at the 3' end of exon 2, leading to exon skipping and splicing of exon 1 to exon 3; the aberrantly spliced messenger RNA contains a frameshift, resulting in premature termination of translation. The present report provides evidence of molecular genetic heterogeneity in white patients with muscle lactate dehydrogenase deficiency.

Muscle recruitment variations during wrist flexion exercise: MR evaluation.

OBJECTIVE: Many exercise protocols used in physiological studies assume homogeneous and diffuse muscle recruitment. To test this assumption during a "standard" wrist flexion protocol, variations in muscle recruitment were assessed using MRI in eight healthy subjects. MATERIALS AND METHODS: Variations were assessed by comparing the right to the left forearms and the effect of slight (15 degrees) pronation or supination at the wrist. RESULTS: Postexercise imaging showed focal regions of increased signal intensity (SI), indicating relatively strong recruitment, most often in entire muscles, although occasionally only in subvolumes of muscles. In 15 of 26 studies, flexor carpi radialis (FCR) showed more SI than flexor carpi ulnaris, while in 11 studies SI in these muscles increased equivalently. Relatively greater FCR recruitment was seen during pronation and/or use of the nondominant side. Palmaris longus, a wrist flexor, did not appear recruited in 4 of 11 forearms in which it was present. A portion of the superficial finger flexor became hyperintense in 89% of studies, while recruitment of the deep finger flexor was seen only in 43%. CONCLUSION: Inter- and intraindividual variations in forearm muscle recruitment should be anticipated in physiological studies of standard wrist flexion exercise protocols.