Exercise efficiency impairment in metabolic myopathies.

Metabolic myopathies are muscle disorders caused by a biochemical defect of the skeletal muscle energy system resulting in exercise intolerance. The primary aim of this research was to evaluate the oxygen cost (∆V'O2/∆Work-Rate) during incremental exercise in patients with metabolic myopathies as compared with patients with non-metabolic myalgia and healthy subjects. The study groups consisted of eight patients with muscle glycogenoses (one Tarui and seven McArdle diseases), seven patients with a complete and twenty-two patients with a partial myoadenylate deaminase (MAD) deficiency in muscle biopsy, five patients with a respiratory chain deficiency, seventy-three patients with exercise intolerance and normal muscle biopsy (non-metabolic myalgia), and twenty-eight healthy controls. The subjects underwent a cardiopulmonary exercise test (CPX Medgraphics) performed on a bicycle ergometer. Pulmonary V'O2 was measured breath-by-breath throughout the incremental test. The ∆V'O2/∆Work-Rate slope for exercise was determined by linear regression analysis. Lower oxygen consumption (peak percent of predicted, mean ± SD; p < 0.04, one-way ANOVA) was seen in patients with glycogenoses (62.8 ± 10.2%) and respiratory chain defects (70.8 ± 23.3%) compared to patients with non-metabolic myalgia (100.0 ± 15.9%) and control subjects (106.4 ± 23.5%). ∆V'O2/∆Work-Rate slope (mLO2.min-1.W-1) was increased in patients with MAD absent (12.6 ± 1.5), MAD decreased (11.3 ± 1.1), glycogenoses (14.0 ± 2.5), respiratory chain defects (13.1 ± 1.2), and patients with non-metabolic myalgia (11.3 ± 1.3) compared with control subjects (10.2 ± 0.7; p < 0.001, one-way ANOVA). In conclusion, patients with metabolic myopathies display an increased oxygen cost during exercise and therefore can perform less work for a given VO2 consumption during daily life-submaximal exercises.

Gas exchange responses to constant work-rate exercise in patients with glycogenosis type V and VII.

During constant work-rate exercise above the lactic acidosis threshold, oxygen consumption fails to plateau by 3 minutes, but continues to rise slowly. This slow component correlates closely with the rise in lactate in normal subjects. We investigated if oxygen consumption during constant work-rate exercise could rise after 3 minutes in the absence of a rise in lactate. We studied five patients with McArdle's disease, one patient with phosphofructokinase deficiency and six normal subjects. Subjects performed two 6-minute duration constant work-rate exercise tests at 40 and 70% of peak oxygen consumption. During low-intensity exercise, oxygen consumption reached steady state by 3 minutes in both groups. Lactate rose slightly in control subjects but not in patients. During high-intensity exercise, oxygen consumption rose from the third to the sixth minute by 144 (21-607) ml/minute (median and range) in control subjects and by 142 (73-306) ml/minute in patients (p = not significant, Mann-Whitney U test). Over the same period, lactate (geometric mean and range) rose from 2.68 (1.10-5.00) to 5.39 (2.70-10.00) mmol/L in control subjects, but did not rise in patients (1.20 [0.64-1.60] to 0.70 [0.57-1.20] mmol/L). We conclude that the slow component of oxygen consumption during heavy exercise is not dependent on lactic acidosis.

No spontaneous second wind in muscle phosphofructokinase deficiency.

OBJECTIVE: The spontaneous second wind in myophosphorylase deficiency (MD, McArdle's disease) represents a transition from low to a higher exercise capacity attributable to increased oxidation of blood-borne fuels, principally glucose and free fatty acids. Muscle phosphofructokinase deficiency (PFKD) blocks the metabolism of muscle glycogen and blood glucose. The authors inquired whether the additional restriction in glucose metabolism in PFKD prevents a spontaneous second wind. METHODS: The authors compared the ability of 29 patients with MD and 5 patients with muscle PFKD to achieve a spontaneous second wind during continuous cycle exercise after an overnight fast. Patients cycled at a constant workload for 15 to 20 minutes (3 MD patients, 3 PFKD patients) and at variable workloads in which peak exercise capacity was determined at 6 to 8 minutes of exercise and again at 25 to 30 minutes of exercise (29 MD patients, 4 PFKD patients). Heart rate was monitored continuously, and perceived exertion (Borg scale) was recorded during each minute of exercise. Oxygen utilization and blood levels of lactate and ammonia were determined at rest and during peak workloads. RESULTS: All variables in both patient groups were similar at 6 to 8 minutes of exercise. Thereafter exercise responses diverged. Each MD patient developed a second wind with a decrease in heart rate and perceived exertion and an increase in work and oxidative capacity. In contrast, no PFKD patient developed a spontaneous second wind. CONCLUSIONS: Patients with muscle phosphofructokinase deficiency are unable to achieve a spontaneous second wind under conditions that consistently produce one in patients with McArdle's disease. The authors conclude that the ability to metabolize blood glucose is critical to the development of a typical spontaneous second wind.

Imbalance of plasma membrane ion leak and pump relationship as a new aetiological basis of certain disease states.

The basis for life is the ability of the cell to maintain ion gradients across biological membranes. Such gradients are created by specific membrane-bound ion pumps [adenosine triphosphatases (ATPases)]. According to physicochemical rules passive forces equilibrate (dissipate) ion gradients. The cholesterol/phospholipid ratio of the membrane and the degree of saturation of phospholipid fatty acids are important factors for membrane molecular order and herewith a determinant of the degree of non-specific membrane leakiness. Other operative principles, i.e. specific ion channels can be opened and closed according to mechanisms that are specific to the cell. Certain compounds called ionophores can be integrated in the plasma membrane and permit specific inorganic ions to pass. Irrespective of which mechanism ions leak across the plasma membrane the homeostasis may be kept by increasing ion pumping (ATPase activity) in an attempt to restore the physiological ion gradient. The energy source for this work seems to be glycolytically derived ATP formation. Thus an increase in ion pumping is reflected by increased ATP hydrolysis and rate of glycolysis. This can be measured as an accumulation of breakdown products of ATP and end-products of anaerobic glycolysis (lactate). In certain disease entities, the balance between ATP formation and ion pumping may be disordered resulting in a decrease in inter alia (i.a.) cellular energy charge, and an increase in lactate formation and catabolites of adenylates. Cardiac syndrome X is proposed to be due to an excessive leakage of potassium ions, leading to electrocardiographic (ECG) changes, abnormal Tl-scintigraphy of the heart and anginal pain (induced by adenosine). Cocksackie B3 infections, a common agent in myocarditis might also induce an ionophore-like effect. Moreover, Alzheimer's disease is characterized by the formation of extracellular amyloid deposits in the brain of patients. Perturbation of cellular membranes by the amyloid peptide during the development of Alzheimer's disease is one of several mechanisms proposed to account for the toxicity of this peptide on neuronal membranes. We have studied the effects of the peptide and fragments thereof on 45Ca2+-uptake in human erythrocytes and the energetic consequences. Treatment of erythrocytes with the beta 1-40 peptide, results in qualitatively similar nucleotide pattern and decrease of energy charge as the treatment with Ca2+-ionophore A23187. Finally, in recent studies we have revealed and published in this journal that a rare condition, Tarui's disease or glycogenosis type VII, primarily associated with a defect M-subunit of phosphofructokinase, demonstrates as a cophenomenon an increased leak of Ca2+ into erythrocytes.

Neurologic and cardiac progression of glycogenosis type VII over an eight-year period.

Little is known about the progression of phosphofructokinase deficiency (glycogenosis type VII, Tarui's disease). We describe a 66-year-old woman who had this disease diagnosed in 1997. Initial manifestations had included simple partial seizures since 1977, anginal chest pain since 1982, and muscle cramps since 1983. To prevent recurrent myocardial infarction, anticoagulation therapy with phenprocumon was initiated. Cardiac involvement progressed over an 8-year period, manifesting as low-voltage electrocardiogram (ECG), ectopic supraventricular tachycardia, thickened mitral valve, mitral valve insufficiency, enlarged left atrium, left ventricular hypertrophy, and diastolic dysfunction. Progression of neurologic involvement manifested as complex partial seizures, double vision, reduced tendon reflexes, central facial palsy, bradydiadochokinesia, and distal weakness of the upper extremities. Discontinuance of oral anticoagulation after 19 years, initiation of enalapril therapy, and administration of carbamazepine markedly improved the patient's condition.

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.

Late-onset muscle weakness in partial phosphofructokinase deficiency: a unique myopathy with vacuoles, abnormal mitochondria, and absence of the common exon 5/intron 5 junction point mutation.

Three patients (ages 51, 59, and 79) from two generations of an Ashkenazi Jewish family had partial (33% activity) phosphofructokinase (PFK) deficiency that presented with fixed muscle weakness after the age of 50 years. MR spectroscopy revealed accumulation of phosphomonoesters during exercise. Muscle biopsy showed a vacuolar myopathy with increased autophagic activity and several ragged-red and cytochrome c oxidase-negative fibers. The older patient, age 79 at biopsy, had several necrotic fibers. Electron microscopy revealed subsarcolemmal and intermyofibrillar glycogen accumulation and proliferation of mitochondria with paracrystalline inclusions, probably related to reduced availability of energy due to impaired glycolysis. The common point mutation of exon 5/intron 5 junction seen in Jewish Ashkenazi patients with PFK deficiency was excluded. We conclude that late-onset fixed muscle weakness occurs in partial PFK deficiency and it may represent the end result of continuing episodes of muscle fiber destruction. Partial enzyme deficiency in two successive generations suggests a unique molecular mechanism.

Improvement of hemolysis in muscle phosphofructokinase deficiency by restriction of exercise.

A 29-year-old woman with muscle phosphofructokinase (PFK) deficiency had exercise intolerance, painful cramps, elevation of muscle enzyme levels in the serum and compensated hemolysis. After the restriction of exercise, the creatine kinase level and indirect bilirubin level decreased, and the reticulocyte count and haptoglobin level were normalized. It is suggested that the hemolysis which was accelerated by exercise was improved by restriction of exercise.

Glucose infusion paradoxically accelerates degradation of adenine nucleotide in working muscle of patients with glycogen storage disease type VII.

We investigated the effect of glucose infusion on adenosine triphosphate degradation in skeletal muscle of patients with glycogen storage disease type VII. Three patients and six healthy subjects exercised on a bicycle ergometer twice, once with 20% glucose infusion and once with saline infusion. The glucose infusion increased plasma glucose levels to 170 to 182 mg/dl and serum insulin levels to 30 to 50 microU/ml, while it markedly decreased plasma free fatty acid levels. The exercise-induced increases in plasma ammonia, inosine, and hypoxanthine were much larger with glucose than with saline infusion in the patients. Urinary excretion of inosine and hypoxanthine with glucose infusion was twice as high as that with saline infusion. No such differences were present between glucose and saline infusion in the healthy subjects. Glucose infusion therefore accelerates the energy crisis in working muscle of patients with glycogen storage disease type VII, probably due to a decrease in fatty acid utilization.

A new variant case of muscle phosphofructokinase deficiency, coexisting with gastric ulcer, gouty arthritis, and increased hemolysis.

Muscle phosphofructokinase (PFK) deficiency includes both clinically and genetically heterogeneous conditions. A 22-year-old man with muscle PFK deficiency due to previously unrecognized mutation was admitted because of gastric ulcer. He had noticed mild fatigability on vigorous exercise, but had never experienced painful cramps and myoglobinuria. His history included five time relapses of gastric ulcer and gouty arthritis at ages 19 and 21 years. His laboratory data showing impaired muscle glycolysis, increased hemolysis, and myogenic hyperuricemia had aspects in common with those reported for the classic form of this disease, except that lactate concentrations in his blood increased considerably after exercise. The mutant PFK enzyme of this patient, who was demonstrated to have a missense mutation, could exert some catalytic activity that permitted glycolytic flux in vivo, thus leading to the absence of typical myopathic symptoms. The association of relapsing gastric ulcer with muscle PFK deficiency was detected for the first time. There is a possibility that oxygen radical-induced tissue damage resulting from increased hypoxanthine on exertion plays a role in the pathogenesis of ulceration, since the patient is more tolerant to exercise than reported cases with the classic form of muscle PFK deficiency.

Erythrocyte glycolysis and its marked alterations by muscular exercise in type VII glycogenosis.

Levels of erythrocyte glycolytic intermediates after the phosphofructokinase (PFK) step, including 2,3-bisphosphoglycerate (2,3-DPG), were decreased at rest in patients from separate families with type VII glycogenosis. The concentration of 2,3-DPG was about half of the normal control value during a period of unrestricted daily activity but was further decreased to one third of normal after a one-day bed rest. Mild ergometric exercise rapidly increased the levels of fructose-1,6-bisphosphate, dihydroxyacetone phosphate plus glyceraldehyde-3-phosphate, and 2,3-DPG in patients' circulating erythrocytes but did not in those of normal subjects. This indicated that a crossover point at the PFK step in glycolysis disappeared after physical exercise and, consequently, the 2,3-DPG concentration, which had decreased because of blockage of the PFK step, was restored considerably. This apparently exercise-related alteration in intermediary metabolism at the beginning of glycolysis was reproduced in vitro by incubating normal erythrocytes in the presence of inosine or ammonia, both of which have increased levels in circulating blood during and after exercise in this disorder. We conclude that physical activity in addition to a genetic deficiency in erythrocyte PFK affects glycolysis in erythrocytes in type VII glycogenosis and that myogenic factors released from exercising muscles may be responsible for this change.