Effect of fuels on exercise capacity in muscle phosphoglycerate mutase deficiency

BACKGROUND: Muscle phosphoglycerate mutase deficiency (PGAMD) is a rare, recessively inherited metabolic myopathy that affects one of the last steps of glycolysis. Clinically, PGAMD resembles muscle phosphorylase deficiency (McArdle disease) and phosphofructokinase deficiency (PFKD). However, it is unknown whether PGAMD is associated with a second-wind phenomenon during exercise, as in McArdle disease, and whether patients with PGAMD, like patients with PFKD and McArdle disease, benefit from supplementation with fuels that bypass the metabolic block. OBJECTIVE: To investigate whether fuels that bypass the metabolic block can improve exercise capacity or whether exercise capacity improves during sustained exercise. DESIGN: Single-blind, placebo-controlled investigation of the effects of glucose, lactate, and intralipid on work capacity in patients with PGAMD. SETTING: National University Hospital, University of Copenhagen, and Neuromuscular Center, Institute for Exercise and Environmental Medicine.Patients Two unrelated men (21 and 26 years old) with PGAMD who since their teens had experienced muscle cramps, muscle pain, and episodes of myoglobinuria provoked by brief vigorous exercise, 4 patients with McArdle disease (mean +/- SD age, 32 +/- 5 years) with 0% residual phosphorylase activity in muscle, and 6 healthy, untrained male volunteers (mean +/- SD age, 23 +/- 1 years) were studied. INTERVENTIONS: Using constant and variable workload protocols on a cycle ergometer, it was investigated whether a spontaneous second wind occurs during exercise in patients with PGAMD, and using a constant workload protocol followed by an incremental load to exhaustion, it was tested whether infusion of lactate, glucose, or intralipid alters the exercise tolerance in PGAMD. MAIN OUTCOME MEASURES: Whether a second wind occurs during exercise and whether fuels that bypass the metabolic block can improve exercise and oxidative capacity. RESULTS: In contrast to patients with McArdle disease, with whom they share many clinical features, in patients with PGAMD, cycle exercise and oxidative capacity are virtually normal, a second wind does not occur, and lipid and lactate supplements do not improve exercise capacity. CONCLUSION: Although the clinical manifestations of PGAMD mimic McArdle disease with respect to the presence of exertional muscle cramps, rhabdomyolysis, and myoglobinuria, this study shows that cycle exercise responses are strikingly different.     

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

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

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.     

Muscle phosphoglycerate mutase deficiency

A 52-year-old man complained since adolescence of cramps and pigmenturia after 15 to 30 minutes of intense exercise. There was no family history of neuromuscular diseases, and strength was normal. The rise of venous lactate after forearm ischemic exercise was abnormally low. Histochemical and ultrastructural studies of a muscle biopsy showed mild increase of glycogen, which was confirmed by biochemical analysis. Studies of anaerobic glycolysis in vitro showed decrease lactate formation with glycogen and with all hexosephosphate glycolytic intermediates, suggesting a defect below the phosphofructokinase reaction. Muscle phosphoglycerate mutase (PGAM) activity was 5.7% of the lowest control, while all other enzymes of glycolysis had normal activities. Electrophoretic, heat lability, and mercury inhibition studies showed that the small residual activity of PGAM in the patient's muscle was represented by the brain (BB) isoenzyme, suggesting a genetic defect of the M subunit that predominates in normal muscle. The prevalence of the BB isoenzyme in other tissues, including muscle culture, may explain why symptoms were confined to muscle.     

Phosphoglycerate kinase deficiency: Another cause of recurrent myoglobinuria

A 14-year-old boy had myoglobinuria and renal failure after intense exercise; a year earlier he had experienced a milder episode. There was no consanguinity and no family history of neuromuscular diseases or hemolytic anemia. Strength was normal. Forearm ischemic exercise caused prolonged contracture with no rise of venous lactate. Muscle morphology showed only a mild increase of lipid droplets. Glycogen concentration was normal. Muscle phosphoglycerate kinase (PGK) activity was 5% of the normal mean, and all other glycolytic enzymes were normal. The residual PGK activity of muscle was heat stable but showed slower than normal electrophoretic mobility and decreased Michaelis constants for 3-phosphoglycerate and adenosine triphosphate. The enzyme defect was also expressed in erythrocytes and in fibroblast and muscle cultures. PGK activity was decreased in tissues from the patient's mother but normal in the father. PGK deficiency is an X-linked recessive trait usually associated with hemolytic anemia, mental retardation, and seizures; myopathy had not been recognized previously. Muscle PGK deficiency is now added to two other newly recognized glycolytic defects, phosphoglycerate mutase and lactate dehydrogenase deficiencies, as a cause of recurrent myoglobinuria.     

Exercise-induced cramp, myoglobinuria, and tubular aggregates in phosphoglycerate mutase deficiency

We report two patients in whom phosphoglycerate mutase (PGAM) deficiency was associated with the triad of exercise-induced cramps, recurrent myoglobinuria, and tubular aggregates in the muscle biopsy. Serum creatine kinase (CK) levels were elevated between attacks of myoglobinuria. Forearm ischemic exercise tests produced subnormal increases of venous lactate. Muscle biopsies showed subsarcolemmal tubular aggregates in type 2 fibers. Muscle PGAM activities were markedly decreased (3% of the normal mean) and molecular genetic studies showed that both patients were homozygous for a described missense mutation (W78X). A review of 15 cases with tubular aggregates in the muscle biopsies from our laboratory and 15 cases with PGAM deficiency described in the literature showed that this clinicopathological triad is highly suggestive of PGAM deficiency.     

Biochemical analysis using biopsied muscle in 72 patients with metabolic myopathies

Biochemical analysis using biopsied muscle specimens was performed on 72 cases who had symptoms suggesting metabolic myopathies. Sixteen out of 72 cases (22%) were diagnosed as having chemically confirmed metabolic defects. Of these 16 cases, 9 had defects in the glycolytic pathway (glycogen storage disease type II; 3 cases, type III; 1 case, type V; 3 cases, phosphoglycerate kinase deficiency; 1 case, phosphoglucomutase deficiency; 1 case) and 7 cases in mitochondrial metabolism (complex IV deficiency; 4 cases, carnitine deficiency; 3 cases). Among 14 cases who were strongly suspected as having a defect in the glycolytic pathway because of abnormal ischemic forearm test, 6 (43%) showed biochemically proved glycolytic defects. These data suggest that care should be taken when evaluating the results of ischemic forearm test. In addition, we should carefully interpret the muscle histochemistry, because histochemical stains including PAS might be fairly normal in the defects with second step glycolytic pathway.     

Ischemic exercise test: failure to detect partial expression of McArdle's disease

The forearm ischemic exercise test (FIET) is a very important clinical tool for evaluation of patients suspected to have a metabolic disorder of muscle function. Failure to elevate lactate in blood washed out from ischemically exercised muscles confirms an abnormality of glycolytic metabolism. A normal increase of lactate on FIET is assumed to rule out a disorder of glycolytic metabolism. Two patients with low levels of muscle phosphorylase are presented who produced a normal elevation of lactate on FIET. This suggests that, although the FIET is capable of identifying patients with absence of myophosphorylase, the test cannot identify patients with a partial expression of that disorder. Evaluation of the blood samples for ammonia in addition to lactate can be a significant help in confirming that the exercise performed by the patient was an adequate challenge for the glycolytic pathway. In addition, failure to elevate ammonia on ischemic exercise can identify a relatively new disorder of muscle metabolism.     

1H and 31P magnetic resonance spectroscopy study of a case of phosphoglycerate kinase deficiency]

Magnetic resonance spectroscopy (MRS) is a useful tool for detecting in vivo metabolic status and in vitro analysis of chemical metabolites. We performed MRS on a 15 year-old mentally retarded male patient with recurrent myoglobinuria due to phosphoglycerate kinase (PGK) deficiency. Muscle histochemistry was normal, although electron microscopy showed a significant increase in glycogen content. Biochemical analysis using muscle specimens revealed profound reduction of PGK activity to 4.4% of the control mean. In vivo MRS using 31P revealed a significant accumulation of sugar phosphates after ischemic forearm exercise, although no significant rise of inorganic phosphate was demonstrated during exercise. 1H MRS using the perchloric acid extracts of the blood taken at the ischemic forearm test, revealed no rise of venous lactate but a significant reduction of alanine levels. These data suggest that, unlike the patients with a glycogenolytic block, our patient with a distal glycolytic block shows a significant accumulation of sugar phosphates. The reason of the reduction of alanine levels was uncertain. A compensatory mechanism for energy supply to the muscle tissue was considered.     

Physiologic assessment of phosphoglycerate mutase deficiency: incremental exercise test

A third case of phosphoglycerate mutase (PGAM) deficiency, a metabolic myopathy involving terminal glycolysis, was identified in a 24-year-old black man with episodic, exercise-induced myoglobinuria since age 13. To better understand the physiologic consequences of PGAM deficiency, incremental exercise testing was performed. Results were compared with those of two patients having myophosphorylase deficiency and five normals. In contrast to the patients with phosphorylase deficiency, the PGAM-deficient patient achieved near-normal levels of maximal exercise and produced a normal peak lactate after exercise. The mechanisms underlying the asymptomatic performance of such strenuous exercise in this case are uncertain, but the data suggest that unidentified factors are operative in precipitating attacks of myoglobinuria in patients with some metabolic myopathies. Despite similar clinical histories, patients with different glycolytic enzyme deficiencies can have striking differences in exercise tolerance.     

A forearm exercise screening test for mitochondrial myopathy

BACKGROUND: The authors hypothesized that impaired oxygen extraction in mitochondrial myopathy (MM) results in a high oxygen saturation in venous effluent blood from working muscle and that this phenomenon can be used as a diagnostic tool for MM. METHODS: Twelve patients with MM, 10 patients with muscular dystrophy, and 12 healthy subjects were studied. All subjects performed intermittent static handgrip exercise (1/2 Hz) at 40% of maximal voluntary contraction (MVC) for 3 minutes. Cubital venous oxygen saturation and brachial artery flow were measured in the exercised arm. RESULTS: Exercise-induced venous oxygen desaturation was smaller in patients with MM (Delta - 7 +/- 5%) than in subjects with muscular dystrophy (Delta - 38 +/- 2%; p = 0.00001) and healthy subjects (Delta - 43 +/- 2%; p = 0.0000002). MVC and exercise blood flow were similar in patients with MM (18 +/- 3 kg; 436 +/- 65 mL/min) and patients with muscular dystrophy (15 +/- 3 kg; 460 +/- 85 mL/min), but were higher in healthy subjects (32 +/- 4 kg; 630 +/- 58 mL/min; p < 0.03). In seven patients with MM and seven patients with McArdle disease, studied with a slightly different protocol, exercise-induced oxygen desaturation was also impaired in MM (Delta - +/- 5%) compared with McArdle disease (Delta - 26 +/- 3%; p = 0.007). CONCLUSION: Oxygen desaturation in venous blood from exercising muscle is markedly lower in patients with mitochondrial myopathy than in subjects with other muscle diseases and healthy subjects, suggesting that a forearm exercise test can be a diagnostic screening tool for mitochondrial myopathy.     

A comparative study on glucagon effect between McArdle disease and Tarui disease

Pretreatment with glucagon relieved patients with McArdle disease from muscular symptoms during exercise and enhanced exercise performance, though it did not produce any improvement in patients with Tarui disease. The difference in glucagon effect between the two diseases was clearly demonstrated in the bicycle ergometer exercise tests. In addition, the semi-ischemic forearm exercise tests performed after glucagon injection showed that increased lactate production was significantly induced by exercise in McArdle disease, but it was not the case in Tarui disease. In McArdle disease, the augmentation in exercise-induced lactate production was also observed after administration of glucose, or glucose plus insulin, but it was neither observed after administration of insulin alone nor after arginine or epinephrine administration. These findings suggest that the beneficial effect of glucagon in McArdle disease is due to the enhanced utilization of circulating glucose through the muscular glycolytic pathway realized in the coexistence of hyperglycemia and hyperinsulinemia.     

Venous oxygen levels during aerobic forearm exercise: An index of impaired oxidative metabolism in mitochondrial myopathy.

A cardinal feature of impaired skeletal muscle oxidative metabolism in mitochondrial myopathies is a limited ability to increase the extraction of O(2) from blood relative to the increase in O(2) delivery by the circulation during exercise. We investigated whether aerobic forearm exercise would result in an abnormal increase in venous effluent O(2) in patients with impaired skeletal muscle oxidative phosphorylation attributable to mitochondrial disease. We monitored the partial pressure of O(2) (PO(2)) in cubital venous blood at rest, during handgrip exercise, and during recovery in 13 patients with mitochondrial myopathy and exercise intolerance and in 13 healthy control and 11 patient control subjects. Resting and recovery venous effluent PO(2) were similar in all subjects, but during exercise venous PO(2) paradoxically rose in mitochondrial myopathy patients from 27.2 +/- 4.0mmHg to 38.2 +/- 13.3mmHg, whereas PO(2) fell from 27.2 +/- 4.2mmHg to 24.2 +/- 2.7mmHg in healthy subjects and from 27.4 +/- 9.5mmHg to 22.2 +/- 5.2mmHg in patient controls. The range of elevated venous PO(2) during forearm exercise in mitochondrial myopathy patients (32 to 82mmHg) correlated closely with the severity of oxidative impairment as assessed during cycle exercise. We conclude that measurement of venous PO(2) during aerobic forearm exercise provides an easily performed screening test that sensitively detects impaired O(2) use and accurately assesses the severity of oxidative impairment in patients with mitochondrial myopathy and exercise intolerance.     

The ischemic exercise test in normal adults and in patients with weakness and cramps

Data from 23 normal men and women were used to derive 95% confidence limits for maximum changes in ammonia and lactate values following ischemic forearm exercise. Most normal subjects raised serum lactate and ammonia concentrations more than 20 mg/dl and 100 micrograms/dl, respectively, over baseline values. No significant correlations were found among age, sex, duration of exercise, or estimate of work performed and the maximum ammonia and lactate values achieved. When 70 patients with complaints of weakness, fatigue, or cramps were evaluated, the ischemic exercise test identified 5 patients who proved to have defects in glycolysis or purine metabolism. The test also distinguished those patients with type III glycogen storage disease who lacked debrancher enzyme activity in muscle.     

Muscle phosphoglycerate mutase (PGAM) deficiency: a second case

Muscle phosphoglycerate mutase (PGAM) activity was markedly decreased (6% of the normal mean) in a 17-year-old girl with recurrent myoglobinuria after intense exercise. Muscle biopsy showed increased PAS stain; glycogen concentration was twice normal. Studies of anaerobic glycolysis in vitro showed decreased lactate production with glycogen, and with all hexose phosphate glycolytic intermediates, which was corrected by addition of purified PGAM to the reaction mixtures. A defect of the M subunit of PGAM was documented by electrophoretic, heat lability, and mercury inhibition studies. Intermediate PGAM activities (39 and 50% of normal) were found in muscle biopsies from the patient's asymptomatic parents. These data confirm the clinical, morphologic, and biochemical features described in the first patient with PGAM deficiency and suggest autosomal-recessive transmission of the trait.     

Iodoacetate inhibition of glyceraldehyde-3-phosphate dehydrogenase as a model of human myophosphorylase deficiency (McArdle's disease) and phosphofructokinase deficiency (Tarui's disease)

A model of the human neuromuscular disorders myophosphorylase deficiency and phosphofructokinase deficiency has been developed using intra-aortic injection of sodium iodoacetate in adult male rats. Iodoacetate selectively inhibits in vivo the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase. The iodoacetate-injected rats develop electrically silent cramps in leg musculature during ischemic (or vigorous non-ischemic) exercise. Post-exercise rhabdomyolysis is evidenced by a 10-fold serum CPK elevation, excessive uptake of ^99mTc-diphosphonate by cramped muscle, and type IIB fiber damage (histochemically-demonstrated) in cramped muscle. Further analysis of this model will allow a greater understanding of the clinical syndrome associated with the human disorders and permit development of successful treatment programs.     

Myopathies Related to Glycogen Metabolism Disorders

Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes in glycogenolysis (myophosphorylase (PYGM), glycogen debranching enzyme (AGL), phosphorylase b kinase (PHKB)) and glycolysis (phosphofructokinase (PFK), phosphoglycerate mutase (PGAM2), aldolase A (ALDOA), β-enolase (ENO3)); however, 3 involve glycogen synthesis (glycogenin-1 (GYG1), glycogen synthase (GSE), and branching enzyme (GBE1)). Many present with exercise-induced cramps and rhabdomyolysis with higher-intensity exercise (i.e., PYGM, PFK, PGAM2), yet others present with muscle atrophy and weakness (GYG1, AGL, GBE1). A failure of serum lactate to rise with exercise with an exaggerated ammonia response is a common, but not invariant, finding. The serum creatine kinase (CK) is often elevated in the myopathic forms and in PYGM deficiency, but can be normal and increase only with rhabdomyolysis (PGAM2, PFK, ENO3). Therapy for glycogen storage diseases that result in exercise-induced symptoms includes lifestyle adaptation and carefully titrated exercise. Immediate pre-exercise carbohydrate improves symptoms in the glycogenolytic defects (i.e., PYGM), but can exacerbate symptoms in glycolytic defects (i.e., PFK). Creatine monohydrate in low dose may provide a mild benefit in PYGM mutations.     

Manifesting heterozygotes in a Japanese family with a novel mutation in the muscle-specific phosphoglycerate mutase (PGAM-M) gene.

Muscle-specific phosphoglycerate mutase (PGAM-M) deficiency results in a metabolic myopathy (glycogenosis type X). Three mutations in the PGAM-M gene have been described thus far, two in African-American families and one in a Caucasian family. In two of them, manifesting heterozygotes were documented. We found a new PGAM-M mutation in a Japanese family with partial PGAM deficiency: a G-to-A transition at nucleotide position 209, resulting in the substitution of a highly conserved glycine at codon 97 with aspartic acid (G97D). Two heterozygous family members for the G97D mutation presented with exercise intolerance and muscle cramps. We describe the first PGAM-M mutation in the Japanese population and confirm that heterozygous individuals can be symptomatic.     

Novel mutation in the PYGM gene resulting in McArdle disease

BACKGROUND: McArdle disease is a common metabolic disorder characterized by marked exercise intolerance, premature fatigue during exertion, myalgia, and cramps. Despite the wide knowledge of the molecular basis of McArdle disease, few studies have used a physiological approach or explored the possibility of improving the exercise capacity of these patients. OBJECTIVES: To describe 3 unrelated patients with McArdle disease with a novel mutation in the PYGM gene and to assess the physical capacity in 1 of them. DESIGN: Using molecular genetic approaches, we identified the underlying molecular defect in 3 patients with McArdle disease. Physical performance was evaluated in 1 patient by means of an exercise tolerance test on a bicycle ergometer. SETTING: Two university hospitals. Exercise physiology studies were performed in a university department. Patients The 3 patients showed common features of McArdle disease. They were definitively diagnosed by histochemistry, biochemistry, or molecular genetic analysis. RESULTS: All of the 3 patients were genetic compounds for the common Arg50Stop mutation and a novel c.13_14delCT mutation in the PYGM gene. The peak oxygen uptake (VO(2peak)) of the patient who performed the exercise test was only 20.2 mL x kg(-1) x min(-1). CONCLUSIONS: Together with the novel mutation, there is a markedly decreased exercise capacity in a patient with McArdle disease, which could account for the profound alteration in the capacity for performing normal activities of daily living in this subpopulation.     

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

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