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.

Muscle phosphoglycerate mutase deficiency (PGAMD) is a rare, recessively inherited metabolic myopathy that affects one of the last steps of glycolysis.¹ The condition is associated with exercise-induced cramps and myoglobinuria, elicited by brief vigorous exercise.^1-4 The enzymatic defect in PGAMD is attributable to mutations in the M isoform of the PGAM gene. Residual PGAM activity in the muscles of patients (typically 2%-6%) is due to activity of the B-isoform.^2,4

Clinically, PGAMD resembles muscle phosphorylase deficiency (McArdle disease) and phosphofructokinase deficiency (PFKD). Patients with McArdle disease and PFKD have complete enzymatic blocks; consequently, their exercise and oxidative capacity improves considerably when fuels that bypass the metabolic block are administered.^5-7 In PGAMD, it is unknown whether such fuels can improve exercise capacity or whether exercise capacity improves during sustained exercise, as is typical with the spontaneous second wind in patients with McArdle disease.⁸ We investigated this in 2 patients with PGAMD and compared findings with those in healthy patients and patients with McArdle disease.

We studied 2 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. Ischemic forearm exercise evoked blunted increases in venous plasma lactate levels and exaggerated increases in plasma ammonium levels. Both had tubular aggregates in muscle. The parents of one patient were first cousins. Both had a selective PGAM deficiency in muscle (approximately 3% of normal). Four 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 also studied. In all of the patients, neurological examination results were normal.

Peak oxygen uptake (V̇O₂max) and cardiac output (Q̇), assessed by the acetylene-rebreathing method, were determined as previously descibed.⁹ Peak arteriovenous oxygen difference (a measure of the integrity of muscle oxidative phosphorylation) was determined as the quotient V̇O₂/Q̇.⁹

The 2 patients with PGAMD and the 3 patients with McArdle disease were studied with an exercise protocol that we have used to delineate the second-wind phenomenon in McArdle disease.⁵ In short, initial peak work and oxidative capacity was determined in the first 6 to 8 minutes of cycle exercise. The workload was then reduced for 5 to 10 minutes in the period when patients with McArdle disease develop a second wind and increased again to determine peak exercise capacity at 20 minutes of exercise. A bolus infusion of 100 mL of 50% glucose was administered to determine the presence of a glucose-induced second wind.⁵ Exercise was stopped at 25 minutes.

One patient with PGAMD was given an infusion of saline, lactate, intralipid, or glucose on separate days. The patient cycled at 65% of V̇O₂max (100 W) for 20 minutes followed by incremental exercise to exhaustion. A group of 6 healthy age-matched men and 1 patient with McArdle disease performed the same exercise protocol during saline (healthy patients and patient with McArdle disease) or glucose (patient with McArdle disease) infusions. Infusions were blinded to the subjects and were started 2 minutes before exercise and primed by a bolus (glucose, 50 mL of a 10% solution; lactate, 50 mL of a 200mM solution; saline, 50 mL; and intralipid, 10 mL with heparin added to promote lipolysis). Constant-rate infusions, using the same solutions as the bolus, were 5 mL/min for glucose, lactate, and saline and 1 mL/min for intralipid.

Phosphorous magnetic resonance spectroscopy (MRS) of the tibialis anterior muscle was performed in the patients with PGAMD at rest and during exercise (intermittent static contractions at 1 Hz) at moderate (30% of maximal voluntary contraction) and high-intensity (45% of maximal voluntary contraction) exercise. Phosphorous MRS recordings were performed as previously described.¹⁰

During maximal work, patients with PGAMD had a normal oxygen extraction capacity (peak arteriovenous difference in oxygen), a normal relationship between blood flow and V̇O₂ (Q̇/V̇O₂), near-normal lactate levels, and a V̇O₂max that was 70% of controls (ie, in the low normal range) (Table). In contrast, patients with McArdle disease had a V̇O₂max that was one third of normal, impaired oxygen extraction capacity, a high Q̇ relative to V̇O₂, and a decrease (mean ± SD, 1.8 ± 0.9 mg/dL [0.2 ± 0.1 mmol/L]) in plasma lactate levels with exercise.

During the variable workload protocol, peak exercise capacity did not change in patients with PGAMD as it did in patients with McArdle disease, thus demonstrating absence of a spontaneous or glucose-induced second wind in PGAMD (Figure 1A). Similarly, during saline infusions, the heart rate was stable during constant workload exercise in patients with PGAMD and healthy subjects, in contrast to the characteristic decrease in heart rate with a spontaneous second wind observed in patients with McArdle disease (Figure 1B and C).

Lactate, glucose, and intralipid infusions more than doubled plasma levels of these substrates in the patients with PGAMD but did not affect exercise capacity based on V̇O₂max and heart rate responses (Figure 1B). In contrast, a glucose infusion induced a new second wind during both the variable (Figure 1A) and constant (Figure 1C) workload protocols in patients with McArdle disease. Plasma lactate levels at the end of the saline infusion protocol were similar in the patients with PGAMD (58.56 mg/dL [6.5 mmol/L]) and the 6 healthy subjects (mean ± SD, 60.36 ± 6.31 mg/dL [6.7 ± 0.7 mmol/L]).

Phosphorous MRS findings in the 2 patients with PGAMD were normal at rest and were similar during exercise, as illustrated in 1 patient (Figure 2). A large peak at 10.7 ppm appeared during high-intensity exercise, reflecting monophosphorylated carbohydrate intermediates (phosphomonoesters [PMEs]). The PME peak did not develop during moderate work but developed during 5½ minutes of exercise to exhaustion at the high work intensity so that the PME concentration reached 18 mmol/L. At exhaustion, the inorganic phosphate peak had increased from 1.5 to 12 mmol/L, the phosphocreatine peak had decreased from 22 to 4.5 mmol/L, and the adenosine triphosphate peak had decreased from 7.5 to 3 mmol/L. As estimated from the chemical shift of inorganic phosphate, the pH dropped from 7.05 at rest to 6.5 at exhaustion. The adenosine triphosphate and pH values did not change in the muscle during moderate work.

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. The principal findings are that (1) patients with PGAMD have near-normal maximal oxidative capacity; (2) they produce almost normal amounts of lactate during dynamic and static intermittent exercise; (3) they do not experience a second wind during exercise, either spontaneously or induced by fuels that bypass the metabolic block; (4) glucose infusion does not impair exercise capacity as it does in patients with PFKD; and (5) PMEs accumulate in muscle exclusively during high-intensity exercise.

The relatively preserved capacity for dynamic exercise in patients with PGAMD undoubtedly relates to the residual enzyme activity that provides sufficient glycolytic flux to meet muscle oxidative requirements at near-maximal work intensities. Accordingly, patients with PGAMD had normal increases in plasma lactate levels and normal phosphorous MRS–assessed acidification of muscle during maximal exercise. Normal lactate responses to maximal cycle exercise and a near-normal work capacity have previously been reported in 1 patient with PGAMD.³ Normal glycolytic flux during submaximal exercise was further evidenced by the absence of PMEs in muscle during moderate exercise intensity, as assessed by phosphorous MRS.

The glycolytic flux necessary to provide sufficient pyruvate to meet oxidative requirements of working muscle is modest compared with that required for sustaining peak rates of adenosine triphosphate production during maximal exercise.⁵ The complete enzymatic blocks present in patients with McArdle disease and PFKD significantly limit peak rates of muscle oxidative phosphorylation. Consequently, muscle oxidative capacity in these conditions depends on the availability of bloodborne fuels that can bypass the metabolic blocks. Therefore, patients with McArdle disease and PFKD experience variations in exercise capacity according to the availability of these fuels,^5,6 epitomized by the second-wind phenomenon in McArdle disease⁸ and the out-of-wind phenomenon in PFKD.⁷ Our results indicate that the residual PGAM activity in PGAMD is sufficient to maintain a glycolysis that meets oxidative requirements and thus eliminates spontaneous fluctuations in exercise capacity (no spontaneous second wind) and fluctuations in exercise capacity induced by supplementation with free fatty acids, lactate, and glucose (no substrate-induced second wind or out of wind). The fact that symptoms of muscle contracture and rhabdomyolysis occur in patients with PGAMD only with intense exercise implicates the metabolic consequences of limited substrate-level phosphorylation during anaerobic glycolysis in the genesis of these symptoms.

Correspondence: John Vissing, MD, PhD, Neuromuscular Clinic, Department of Neurology 2082, National University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark (vissing@rh.dk).

Accepted for Publication: November 22, 2004.

Author Contributions:Study concept and design: Vissing and Haller. Acquisition of data: Vissing, Quistorff, and Haller. Analysis and interpretation of data: Vissing, Quistorff, and Haller. Drafting of the manuscript: Vissing. Critical revision of the manuscript for important intellectual content: Vissing, Quistorff, and Haller. Statistical analysis: Vissing. Obtained funding: Vissing, Quistorff, and Haller. Administrative, technical, and material support: Vissing, Quistorff, and Haller.

Funding/Support: The study was financially supported by grant 504-14 from the Danish National Research Foundation, Copenhagen; the Muscular Dystrophy Association, Tucson, Ariz; and a Veterans Affairs Merit Review.

Acknowledgment: Excellent technical help was performed by Karin Juel, Carsten Bo Nielsen, Marguerite Gunder, and Karen Ayyad.