Original Article
Glucose-Induced Exertional Fatigue in Muscle Phosphofructokinase Deficiency
N Engl J Med 1991; 324:364-369February 7, 1991
- Abstract
Background.
The exercise capacity of patients with muscle phosphofructokinase deficiency is low and fluctuates from day to day. The basis of this variable exercise tolerance is unknown, but our patients with this disorder report that fatigue of active muscles is more rapid after a high-carbohydrate meal.
Methods and Results.
To determine the effect of carbohydrate on exercise performance, we asked four patients with muscle phosphofructokinase deficiency to perform cycle exercise under conditions of differing availability of substrate — i.e., after an overnight fast, and during an infusion of glucose or triglyceride (with 10 U of heparin per kilogram of body weight) after an overnight fast. As compared with fasting and the infusion of triglyceride with heparin, the glucose infusion lowered plasma levels of free fatty acids and ketones, reduced maximal work capacity by 60 to 70 percent, and lowered maximal oxygen consumption by 30 to 40 percent. Glucose also increased the relative intensity of submaximal exercise, as indicated by a higher heart rate at a given workload during exercise. The maximal cardiac output (i.e., oxygen delivery) was not affected by varying substrate availability, but the maximal systemic arteriovenous oxygen difference was significantly lower during glucose infusion (mean ±SE, ±0.3 ml per deciliter) than after fasting (7.6±0.4 ml per deciliter, P<0.05) or during the infusion of triglyceride with heparin (8.9±1.3 ml per deciliter, P<0.05).
Conclusions.
In muscle phosphofructokinase deficiency, the oxidative capacity of muscle and the capacity for aerobic exercise vary according to the availability of blood-borne fuels. We believe that glucose infusion lowers exercise tolerance by inhibiting lipolysis and thus depriving muscle of oxidative substrate (plasma free fatty acids and ketones); this impairs the capacity of working muscle to extract oxygen and lowers maximal oxygen consumption.
Media in This Article
Figure 1
Heart Rate and Respiratory Function during Cycle Exercise in Four Adult Patients with Muscle Phosphofructokinase Deficiency, after Glucose Infusion, Fasting, and Triglyceride-Heparin Infusion. The work intensity for each patient was the same under each set of metabolic conditions: 10 W for Patient 2 (open squres) and Patient 4 (solid squares), 15 W for Patient 1 (open circles), and 18 W for Patient 3 (solid circles).Figure 2
Maximal Work Intensity, Cardiac Output, and Respiratory Function during Maximal Cycle Exercise under the Three Sets of Study Conditions. The four patients are represented by the same symbols used in Figure 1.Article Activity
- Article
PHOSPHOFRUCTOKINASE catalyzes the rate-limiting reaction in glycolysis, the phosphorylation of fructose-6-phosphate to fructose-1,6-diphosphate. An inherited deficiency of the muscle form of phosphofructokinase (muscle phosphofructokinase deficiency, or Tarui's disease) results in a complete block in muscle glycolysis and glycogenolysis, leading to premature muscle fatigue, cramping, and often injury when the muscles' energy demand is increased by exercise.1 Patients with muscle phosphofructokinase deficiency, like those with muscle phosphorylase deficiency (McArdle's disease), have premature fatigue not only during isometric exercise or exercise inducing ischemia but also during dynamic or isotonic exercise.1,2 Dynamic exercise relies predominantly on oxidative metabolism3; studies of normal subjects in whom muscle glycogen has been depleted4 and patients with muscle phosphorylase deficiency5 suggest that the severe reduction in the capacity for dynamic exercise when glycolysis in muscle is impaired is due to the inability to generate pyruvate, the oxidative fuel required to support normal maximal aerobic power.4,5 As a result, persons with this condition are dependent on alternative fuels such as free fatty acids to meet requirements for oxidation in muscle during exercise. In patients with muscle phosphorylase deficiency, exercise capacity varies according to the availability of these alternative, blood-borne oxidative substrates. Epitomizing this substrate-dependent variation in exercise tolerance is the "second-wind" phenomenon, in which previously fatiguing exercise can be performed with relative ease6; this phenomenon is attributable to the increased availability of blood-borne oxidative substrates, particularly free fatty acids.7,8 In patients with muscle phosphorylase deficiency, the infusion of glucose or the administration of agents that stimulate hepatic glycogenolysis and raise the blood glucose levels also improves exercise tolerance by augmenting glucose oxidation by working muscle,9 and some investigators have postulated that increased utilization of glucose by working muscle is crucial for the development of a second wind.10,11
Exercise tolerance also fluctuates in patients with muscle phosphofructokinase deficiency,1,12,13 although some investigators argue that a second wind is unusual in such patients10,11 and suggest that this relates to the fact that utilization of glucose as well as glycogen is blocked in this disorder. To identify and determine the possible basis of variations in exercise capacity in patients with muscle phosphofructokinase deficiency, we studied five such patients; in four of them we measured exercise capacity under conditions of varying substrate availability.
Methods
Patients
The five patients studied were an 18-year-old man (Patient 1) and his 22-year-old sister (Patient 2), a 48-year-old man (Patient 3), and a 17-year-old woman Patient 4) and her 10-year-old brother (Patient 5). The histories obtained from the four younger patients were confirmed by their parents. All the patients were of Ashkenazic Jewish descent, and the four younger patients were members of families that practiced Orthodox Judaism. Each of the five patients had a history of lifelong exercise intolerance with premature muscle fatigue, and each reported occasions on which initially fatiguing cy. Perhaps more vivid, however, was their experience in which exercise that had previously been well tolerated seemed more difficult and produced fatigue more rapidly. Reduced exercise capacity was typically noted after eating, particularly after a meal high in carbohydrates. An example of an experience common to the four younger patients was variable exercise tolerance in walking to synagogue: if they had eaten breakfast, they tired far more easily than if they had fasted. The major symptoms noted after eating were increased susceptibility to fatigue of active muscles, manifested by heaviness or weakness of the limbs and the need to rest frequently. The oldest patient (Patient 3) also had noted that eating a high-carbohydrate meal reduced his exercise tolerance, but he identified increased susceptibility to exertional nausea as his chief symptom.
Three of the four older patients had elevated serum creatine kinase levels. In addition, all the patients had evidence of a partial defect of phosphofructokinase in red cells, an elevated serum bilirubin concentration to 82.1 μmol per liter) or an elevated reticulocyte count (or both), and normal hemoglobin and hematocrit values compatible with a compensated hemolytic anemia. The diagnosis of muscle phosphofructokinase deficiency was established biochemically by the demonstration of an absence of phosphofructokinase in biopsy specimens of skeletal muscle (Patient 1)12 or an absence of the M subunit of phosphofructokinase in red cells (Patients 3, 4, and 5).14 In one patient (Patient 2), the diagnosis was inferred from the presence of symptoms and laboratory findings identical to those in her brother (Patient 1), in whom the diagnosis was confirmed biochemically. Phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy performed during maximal forearm exercise9 in the four older patients revealed the accumulation of a hexose phosphate peak and the absence of a decrease in muscle pH from resting values — findings compatible with a metabolic block at the level of muscle phosphofructokinase.15-17
The four older patients (Patients 1, 2, 3, and 4) were studied at the Clinical Research Center, Southwestern Medical Center. The research protocol was approved by the institutional review board, and informed consent was obtained from the patients or their parents before testing.
Study Protocol
The patients exercised on a pedal-rate—independent cycle ergometer National Aeronautics and Space Administration Skylab ergometer) at submaximal and maximal workloads for 5 to 6 minutes in an ascending order of intensity, with 15 minutes of rest between exercise periods. Maximal exercise was regarded as the highest workload at which cycling could be continued for five minutes. At rest and during the last minute at each workload, expired air was collected in Douglas bags and cardiac output was determined. Ventilation, oxygen uptake, and carbon dioxide production were measured with a Tissot spirometer and a mass spectrometer (Perkin-Elmer 1100A). The ratio of ventilation to oxygen uptake and the respiratory exchange ratio were calculated from data on gas exchange. Cardiac output was measured noninvasively according to the acetylene-rebreathing technique of Triebwasser et al.18 as previously described.19 The systemic arteriovenous oxygen difference was calculated from the Fick equation — i.e., by dividing the oxygen uptake (in milliliters) by the cardiac output (in deciliters). The heart rate was monitored continuously by means of electrocardiographic recordings; the rate recorded during the last minute of exercise was correlated with other responses to exercise.
The patients were tested under three conditions: in the fasting state (after an over-night fast lasting 12 to 14 hours); during an infusion of glucose (10 percent dextrose infused at a rate of 6 ml per minute, beginning 30 minutes before exercise and continuing until the completion of the exercise test) after an overnight fast, to simulate a highcarbohydrate meal; and during an infusion of triglyceride (a 10 percent triglyceride emulsion [Liposyn II, Abbott Laboratories; 5 percent safflower oil and 5 percent soybean oil] infused at a rate of 1 ml per minute, beginning 30 minutes before exercise and continuing until the completion of the exercise test) after an overnight fast, with heparin a total of 10 U per kilogram of body weight given in three intravenous injections at relatively equal intervals during exercise testing), to promote lipolysis and increase plasma levels of free fatty acids.
On the first day, the patients underwent preliminary graded exercise testing followed by a rest period of approximately one hour, during which the glucose infusion was begun, and continued exercise testing during the infusion. On the following day, the exercise workloads completed during the glucose infusion were repeated and maximal work capacity during fasting was determined by means of graded exercise. After a one-hour rest period, during which the infusion of triglyceride with heparin was begun, graded exercise testing was repeated. The patients were not aware that exercise performance was expected to vary with differing metabolic conditions, but they were aware that different substrates were being infused. The number of exercise periods varied as a function of the maximal work capacity under differing metabolic conditions, ranging from one or two periods during glucose infusion to three or four periods during fasting and triglyceride—heparin infusion. Accordingly, the total duration of the exercise sessions (sequential periods of 5 minutes of exercise and 15 minutes of rest) ranged from 20 to approximately 80 minutes.
Venous (antecubital) blood samples were collected in the last minute of each exercise period for the determination of substrate levels. The samples were placed on ice and centrifuged in the cold within 15 minutes, and the plasma was stored frozen at —70°C until assayed. Plasma free fatty acids were measured with a colorimetric assay.20 Plasma ketone (acetoacetic and β-hydroxybutyric acids) and glucose levels were determined enzymatically.21 All plasma samples from each patient were analyzed at the same time in duplicate. The results are expressed as means ±SEM. The statistical significance of differences in values during glucose infusion, fasting, and triglyceride—heparin infusion was determined by repeated-measures one-way analysis of variance. A Newman—Keuls multiple-comparisons test was used to test for specific intergroup differences. A P value below 0.05 was considered to indicate statistical significance.
Results
Glucose infusion approximately doubled plasma glucose levels as compared with levels during fasting or triglyceride—heparin infusion and was associated with the lowest levels of plasma free fatty acids and ketones (Table 1Table 1
Substrate Levels after Five to Six Minutes of Maximal Exercise in Four Adult Patients with Muscle Phosphofructokinase Deficiency, According to Study Conditions.). Triglyceride—heparin infusion resulted in significantly higher plasma levels of free fatty acids and ketones than did fasting or glucose infusion. These variations in substrate availability were associated with substantial differences in the responses to submaximal and maximal exercise.During exercise performed at the same workload (10 W for Patients 2 and 4, 15 W for Patient 1, and 18 W for Patient 3) and with similar oxygen uptake (Table 2Table 2
Cardiac and Respiratory Function during Constant-Workload Exercise in the Four Adult Patients, According to Study Conditions.) under each set of study conditions, the mean heart rate in each patient during glucose infusion was 16 beats per minute higher than during fasting (P<0.05) and almost 30 beats higher than during triglyceride—heparin infusion (P<0.05) (Table 2 and Fig. 1AFigure 1Heart Rate and Respiratory Function during Cycle Exercise in Four Adult Patients with Muscle Phosphofructokinase Deficiency, after Glucose Infusion, Fasting, and Triglyceride-Heparin Infusion. The work intensity for each patient was the same under each set of metabolic conditions: 10 W for Patient 2 (open squres) and Patient 4 (solid squares), 15 W for Patient 1 (open circles), and 18 W for Patient 3 (solid circles).). The mean cardiac output was also significantly higher during glucose infusion than during fasting (P<0.05) or triglyceride—heparin infusion (P<0.05) (Table 2). The level of pulmonary ventilation, the ratio of ventilation to oxygen uptake, and the respiratory exchange ratio were highest during glucose infusion (Fig. 1B through ID). The mean respiratory exchange ratio during glucose infusion, which was significantly higher than during fasting (P<0.05) or triglyceride—heparin infusion (P<0.05), paralleled and was probably caused by the increase in the ratio of ventilation to oxygen uptake during the glucose infusion, rather than by an increase in the oxidation of carbohydrate.Maximal exercise capacity also was altered significantly by interventions that modified the availability of substrate. As was consistent with the patients' histories of decreased exercise tolerance after a highcarbohydrate meal, the maximal work rate and maximal oxygen uptake were lower during glucose infusion (Fig. 2AFigure 2
Maximal Work Intensity, Cardiac Output, and Respiratory Function during Maximal Cycle Exercise under the Three Sets of Study Conditions. The four patients are represented by the same symbols used in Figure 1. and B). The mean maximal work rate during glucose infusion 13.3±2.0 W) was less than half that during fasting (32.5±2.5 W, P<0.05) and less than one third that during triglyceride—heparin infusion ±5.9 W, P<0.05). Correspondingly, the mean maximal oxygen uptake during glucose infusion (10.5±1.5 ml per kilogram per minute) was only percent of uptake during fasting (14.6± 2.9 ml per kilogram per minute, P<0.05) and about 60 percent of uptake during triglyceride—heparin infusion (17.0±2.5 ml per kilogram per minute, P<0.05).To investigate the physiologic basis for the variation in maximal oxygen uptake under these conditions of differing substrate availability, we analyzed the components of oxygen uptake — namely, cardiac output nous oxygen difference (denoting oxygen extraction). The mean maximal cardiac output was similar under each set of conditions (glucose infusion, 191±29 ml per kilogram per minute; fasting, ±40; triglyceride—heparin infusion, 196±46), indicating that maximal oxygen delivery was unaltered by glucose or differences in the availability of fatty acids and ketones (Fig. 2C). In contrast, the mean maximal systemic arteriovenous oxygen difference was significantly smaller during glucose infusion than during fasting or triglyceride—heparin infusion (Fig. 2nd). The low maximal systemic arteriovenous oxygen difference (5.5±0.3 ml per deciliter) during glucose infusion suggests that the high carbohydrate load impaired the capacity of skeletal muscle deficient in phosphofructokinase to extract oxygen from circulating blood. The mean maximal arteriovenous oxygen difference was significantly larger during fasting (7.6±0.4 ml per deciliter) than during glucose infusion (P<0.05); with the marked elevations in plasma levels of free fatty acids and ketones during triglyceride—heparin infusion, oxygen extraction was almost twice that during glucose infusion (8.9±1.3 ml per deciliter, P<0.05). The levels of oxygen extraction during fasting, glucose infusion, and triglyceride—heparin infusion varied in the direction of the changes in the concentrations of free fatty acids and ketones, implying that oxidative metabolism in muscle is linked to the availability of these oxidizable substrates in patients with muscle phosphofructokinase deficiency.
Discussion
The low exercise capacity of patients with muscle phosphofructokinase deficiency correlates with their low maximal oxygen uptake and is consistent with the crucial role of oxidative metabolism in supporting energy needs during dynamic exercise. The maximal oxygen uptake in the patients with this disorder was similar to that in patients with muscle phosphorylase deficiency studied in our laboratory, representing one third to one half the uptake in healthy sedentary subjects (30 to ml per kilogram per minute).22
Maximal oxygen uptake is the product of oxygen delivery and oxygen extraction during maximal exercise. In the patients with muscle phosphofructokinase deficiency, maximal cardiac output was similar to that in healthy sedentary subjects,22 implying that maximal oxygen uptake was not limited by oxygen delivery. In contrast, the maximal systemic arteriovenous oxygen difference in the patients with muscle phosphofructokinase deficiency was low, as reported previously in patients with muscle phosphorylase deficiency.5 These results are consistent with the view that muscle glycogenolysis is essential for the expression of normal maximal aerobic power during exercise.4,5 They also suggest that the block in muscle glycogenolysis that is common to both muscle phosphorylase deficiency and muscle phosphofructokinase deficiency, rather than the impaired glucose metabolism in skeletal muscle or red cells — an additional feature of muscle phosphofructokinase deficiency1 — is the principal mechanism impairing muscle oxidative metabolism. The cellular basis for attenuated maximal oxygen extraction and low maximal oxygen uptake in muscle phosphorylase deficiency has been postulated to be substrate-limited oxidative phosphorylation.23 We propose a similar mechanism to account for the defect in oxidation in patients with muscle phosphofructokinase deficiency.
The block in oxidation of muscle glycogen increases patients' dependence on circulating oxidative substrates to meet energy requirements during exercise. This is illustrated by the marked variation in the capacity for dynamic exercise in patients with muscle phosphorylase deficiency according to the availability of blood-borne fuels. Pearson and coworkers used the term "second wind" to characterize the increase in the capacity for exercise that occurs spontaneously or in response to infusions of carbohydrate or lipid in patients with muscle phosphorylase deficiency.6 The common denominator of a second wind — whether achieved spontaneously, by substrate infusions, or by interventions that augment substrate mobilization,7 muscle blood flow,8 or cellular fuel transport24 — is apparently an increased cellular supply of oxidizable substrate and hence an augmented rate of adenosine triphosphate production through oxidative phosphorylation.9,23 Blood glucose is an important oxidative fuel in muscle phosphorylase deficiency. Increasing the availability of glucose increases the maximal oxygen uptake and the maximal systemic arteriovenous oxygen difference5 and attenuates the decrease in phosphocreatine and the increase in inorganic phosphate in working muscle, as monitored by 31P NMR9 — a finding consistent with enhanced oxidative phosphorylation.
In muscle phosphofructokinase deficiency, in contrast, the utilization of blood glucose is blocked, and therefore lipids represent the primary fuel available for muscular work. The dependence of patients with muscle phosphofructokinase deficiency on lipids as fuel is indicated by the improvement in their exercise performance that accompanied the increase in plasma levels of free fatty acids and ketones during fasting or triglyceride—heparin infusion, as well as by the marked decline in exercise capacity when the levels of free fatty acids and ketones fell during glucose infusion. This glucose-induced decrease in exercise tolerance confirms our patients' experience of increased effort and more rapid fatigue during exercise after a high-carbohydrate meal. Glucose lowered the peak workload that could be attained, and increased the relative intensity of a given level of exercise, as indicated by the higher heart rate and higher ratio of pulmonary ventilation to oxygen uptake in each patient during glucose infusion. Glucose lowered the maximal oxygen uptake by decreasing the maximal systemic arteriovenous oxygen difference without altering maximal cardiac output; this finding is consistent with the hypothesis that glucose impairs exercise performance in patients with muscle phosphofructokinase deficiency by impairing the capacity of working muscle for oxidative phosphorylation. We propose the term "out-of-wind" to characterize this carbohydrateinduced decrease in exercise performance.
The effects of glucose infusion in patients with muscle phosphofructokinase deficiency are in direct contrast to the exercise response to the administration of glucose in patients with muscle phosphorylase deficiency,5-8,25 but they are similar to those produced by the administration of nicotinic acid in patients with muscle phosphorylase deficiency.8,25,26 Both glucose and nicotinic acid inhibit triglyceride hydrolysis and reduce plasma levels of free fatty acids, thus reducing the level of hepatic ketogenesis and the availability of lipid fuels for oxidation by working muscle. The antilipolytic effect of glucose in muscle phosphorylase deficiency is apparently countered by an increase in muscle glucose oxidation, which balances or surpasses the energy deficit that would otherwise accompany a decreased availability of lipid fuels. This formulation is supported by the observation that glucose can produce a second wind in patients with muscle phosphorylase deficiency who are given nicotinic acid.26 In contrast, in patients with muscle phosphofructokinase deficiency glucose produces an unopposed decline in the availability of oxidative substrate and thus a shortage in the oxidative energy supply relative to demand during exercise.
We propose the scheme outlined in Figure 3Figure 3
Postulated Mechanism of the Out-of-Wind Effect Induced by Glucose in Patients with Muscle Phosphofructokinase Deficiency. X denotes the site of the metabolic block in skeletal muscle. The dotted arrows indicate pathways of substrate oxidation that are blocked as a consequence of phosphofructokinase deficiency. Oxidative phosphorylation and oxygen uptake (O2) by muscle are largely dependent on the availability of free fatty acids (FFA) and ketones (produced from FFA in the liver) for the production of acetyl coenzyme A (acetyl CoA) to support oxidative metabolism. Glucose lowers (-) FFA levels, thus depriving muscle of substrate and reducing maximal rates of oxidative phosphorylation and oxygen uptake. ADP denotes adenosine diphosphate, ATP adenosine triphosphate, and Pi inorganic phosphate. to explain the effect of glucose in muscle phosphofructokinase deficiency. The inability to use glycogen or blood glucose makes phosphofructokinase-deficient muscle heavily dependent on fatty acids and ketone bodies as oxidative fuels. Intravenous glucose or dietary carbohydrate lowers plasma levels of free fatty acids and reduces hepatic production of ketones, thus depriving muscle of oxidative substrate. The decline in available substrate reduces the rate of oxidative phosphorylation and impairs muscle oxygen extraction. Conversely, when free fatty acids and ketones are relatively plentiful, the rate of oxidative phosphorylation is augmented, muscle oxygen extraction is increased, and exercise capacity is enhanced. The out-of-wind effect represents an extreme on the continuum of substrate availability, opposite to the extreme represented by the second wind. Both phenomena illustrate that, in the presence of a complete block in glycogen break-down due to muscle phosphorylase or muscle phosphofructokinase deficiency, oxidative metabolism in muscle is paced by access to blood-borne fuels and thus is subject to peaks and valleys of substrate availability according to dietary and other variables that port of these fuels. Glycogen is thus crucial to normal muscle oxidative metabolism both because it is needed to fuel maximal rates of oxidative phosphorylation and because it is the most readily available of muscle oxidative substrates and so buffers against normal fluctuations in the availability of extramuscular fuels during submaximal exercise.Supported by the Department of Veterans Affairs, by the Muscular Dystrophy Association, by grants (HL-06296 and M01-RR-00633) from the National Institutes of Health, and by the Harry S. Moss Heart Center. Dr. Lewis is the recipient of a Research Career Development Award (HL-01581) from the National Institutes of Health.
We are indebted to Dr. Salvatore DiMauro (Department of Neurology, Neurological Institute, Columbia University College of Physicians and Surgeons, New York) for diagnosis and referral in the cases of Patients 1 and 2; to Dr. Shobanna Vora deceased; Scripps Institute, La Jolla, Calif.) for diagnosis and referral in the cases of Patients 3, 4, and 5; to Ms. Marguerite Gunder, Ms. Karen Ayyad, Mr. Paul Gustafson, Mr. Julius Lamar, and Mr. Willie Moore for expert technical assistance; and to Dr. Gunnar Blomqvist for invaluable support.
Source Information
From the Departments of Neurology (R.G.H.) and Physiology (S.F.L.), Department of Veterans Affairs Medical Center, Dallas, and the University of Texas Southwestern Medical Center (R.G.H., S.F.L.), Dallas. Address reprint requests to Dr. Haller at the Neurology Service (127), VA Medical Center, 4500 S. Lancaster, Dallas, TX 75216.
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- Citing Articles (16)
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Alejandro Lucia, Gisela Nogales-Gadea, Margarita Pérez, Miguel A Martín, Antoni L Andreu, Joaquín Arenas. (2008) McArdle disease: what do neurologists need to know?. Nature Clinical Practice Neurology 4:10, 568-577
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S??bastien Ratel, Pascale Duch??, Craig A Williams. (2006) Muscle Fatigue during High-Intensity Exercise in Children. Sports Medicine 36:12, 1031-1065
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Vissing, John, Haller, Ronald G., . (2003) The Effect of Oral Sucrose on Exercise Tolerance in Patients with McArdle's Disease. New England Journal of Medicine 349:26, 2503-2509
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Robert L Wortmann, Salvatore DiMauro. (2002) Differentiating idiopathic inflammatory myopathies from metabolic myopathies. Rheumatic Disease Clinics of North America 28:4, 759-778
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Salvatore DiMauro, Costanza Lamperti. (2001) Muscle glycogenoses. Muscle & Nerve 24:8, 984-999
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Zohar Argov, Mervi L
fberg, Douglas L. Arnold. (2000) Insights into muscle diseases gained by phosphorus magnetic resonance spectroscopy. Muscle & Nerve 23:9, 1316-1334
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Zohar Argov, Douglas L. Arnold. (2000) MR SPECTROSCOPY AND MR IMAGING IN METABOLIC MYOPATHIES. Neurologic Clinics 18:1, 35-52
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Seiichi Tsujino, Ikuya Nonaka, Salvatore DiMauro. (2000) GLYCOGEN STORAGE MYOPATHIES. Neurologic Clinics 18:1, 125-150
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STEPHANIE J. VALBERG, JENNIFER M. MACLEAY, JESSICA A. BILLSTROM, MELISSA A. HOWER-MORITZ, J. R. MICKELSON. (1999) Skeletal muscle metabolic response to exercise in horses with ‘tying-up’ due to polysaccharide storage myopathy. Equine Veterinary Journal 31:1, 43-47
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John C. Kincaid. (1997) MUSCLE PAIN, FATIGUE, AND FASICULATIONS. Neurologic Clinics 15:3, 697-709
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Nina Raben, Jeffrey B. Sherman. (1995) Mutations in muscle phosphofructokinase gene. Human Mutation 6:1, 1-6
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Ikuo Mineo, Seiichiro Tarui. (1995) Myogenic hyperuricemia: What can we learn from metabolic myopathies?. Muscle & Nerve 18:S14, S75-S81
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William Bank, Britton Chance. (1994) An oxidative defect in metabolic myopathies: Diagnosis by noninvasive tissue oximetry. Annals of Neurology 36:6, 830-837
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Ronald G. Haller. (1994) Oxygen Utilization and delivery in metabolic my opathies. Annals of Neurology 36:6, 811-813
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(1991) Exertional Fatigue in Disorders of Muscle. New England Journal of Medicine 324:26, 1896-1897
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Layzer, Robert B., . (1991) How Muscles Use Fuel. New England Journal of Medicine 324:6, 411-412
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