phosphocreatine and Glycogen-Storage-Disease-Type-V

To determine whether treatment with creatine can improve exercise intolerance in myophosphorylase deficiency (McArdle disease).. Double-blind, placebo-controlled crossover study with oral creatine monohydrate supplementation.. Nine patients with biochemically and genetically proven McArdle disease were treated.. Five days of daily high-dose creatine intake (150 mg/kg body weight) were followed by daily low-dose creatine intake (60 mg/kg). Each treatment phase with creatine or placebo lasted 5 weeks.. The effect of treatment was estimated at the end of each treatment phase by recording clinical scores, ergometer exercise test results, phosphorus 31 nuclear magnetic resonance spectroscopy, and surface electromyography.. Of 9 patients, 5 reported improvement of muscle complaints with creatine. Force-time integrals (P =.03) and depletion of phosphocreatine (P =.04) increased significantly during ischemic exercise with creatine. Phosphocreatine depletion also increased significantly during aerobic exercise (P =.006). The decrease of median frequency in surface electromyograms during contraction was significantly larger (P =.03) with creatine.. This is the first controlled study indicating that creatine supplementation improves skeletal muscle function in McArdle disease.

Topics: Administration, Oral; Adult; Child; Creatine; Creatine Kinase; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Electromyography; Energy Metabolism; Exercise Test; Exercise Tolerance; Female; Glycogen Storage Disease Type V; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; Treatment Outcome

Brain and muscle glycogen are generally thought to function as local glucose reserves, for use during transient mismatches between glucose supply and demand. However, quantitative measures show that glucose supply is likely never rate-limiting for energy metabolism in either brain or muscle under physiological conditions. These tissues nevertheless do utilize glycogen during increased energy demand, despite the availability of free glucose, and despite the ATP cost of cycling glucose through glycogen polymer. This seemingly wasteful process can be explained by considering the effect of glycogenolysis on the amount of energy obtained from ATP (ΔG'

Topics: Adenosine Triphosphate; Animals; Astrocytes; Brain; Glycogen; Glycogen Phosphorylase; Glycogen Storage Disease Type V; Glycogenolysis; Humans; Muscle Cells; Muscle, Skeletal; Phosphates; Phosphocreatine; Thermodynamics

It has been suggested that 5'AMP-activated protein kinase (AMPK) is involved in the regulation of glucose and glycogen metabolism in skeletal muscle. We used patients with chronic high muscle glycogen stores and deficient glycogenolysis (McArdle's disease) as a model to address this issue. Six McArdle patients were compared with control subjects during exercise. Muscle alpha2AMPK activity increased in McArdle patients (from 1.3 +/- 0.2 to 1.9 +/- 0.2 pmol min(-1) mg(-1), P = 0.05) but not in control subjects (from 1.0 +/- 0.1 to 1.3 +/- 0.3 pmol min(-1) mg(-1)). Exercise-induced phosphorylation of the in vivo AMPK substrate acetyl CoA carboxylase (ACCbeta; Ser(221)) was higher (P < 0.01) in McArdle patients than in control subjects (18 +/- 3 vs. 10 +/- 1 arbitrary units). Exercise-induced whole-body glucose utilization was also higher in McArdle patients than in control subjects (P < 0.05). No correlation between individual AMPK or ACCbeta values and glucose utilization was observed. Glycogen synthase (GS) activity was decreased in McArdle patients from 11 +/- 1.3 to 5 +/- 1.2 % (P < 0.05) and increased in control subjects from 19 +/- 1.6 to 23 +/- 2.3 % (P < 0.05) in response to exercise. This was not associated with activity changes of GS kinase 3 or protein phosphatase 1, but the changes in GS activity could be due to changes in activity of AMPK or protein kinase A (PKA) as a negative correlation between either ACCbeta phosphorylation (Ser(221)) or plasma adrenaline and GS activity was observed. These findings suggest that GS activity is increased by glycogen breakdown and decreased by AMPK and possibly PKA activation and that the resultant GS activity depends on the relative strengths of the various stimuli. Furthermore, AMPK may be involved in the regulation of glucose utilization during exercise in humans, although the lack of correlation between individual AMPK activity or ACCbeta phosphorylation (Ser(221)) values and individual glucose utilization during exercise implies that AMPK may not be an essential regulator.

Topics: Acetyl-CoA Carboxylase; Adult; AMP-Activated Protein Kinases; Blood Glucose; Exercise; Female; Glucose; Glucose Transporter Type 4; Glycogen; Glycogen Storage Disease Type V; Glycogen Synthase; Hemodynamics; Hormones; Humans; Lactic Acid; Male; Monosaccharide Transport Proteins; Multienzyme Complexes; Muscle Proteins; Muscle, Skeletal; Phosphocreatine; Phosphoprotein Phosphatases; Phosphorylation; Protein Phosphatase 1; Protein Serine-Threonine Kinases; Respiratory Mechanics; Signal Transduction

We studied exercise-induced changes in the adenosine triphosphate (ATP), phosphocreatine (PCr), and lactate levels in the skeletal muscle of mitochondrial patients and patients with McArdle's disease. Needle muscle biopsy specimens for biochemical measurement were obtained before and immediately after maximal short-term bicycle exercise test from 12 patients suffering from autosomal dominant and recessive forms of progressive external ophthalmoplegia and multiple deletions of mitochondrial DNA (adPEO, arPEO, respectively), five patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) 3243 A-->G point mutation, and four patients with McArdle's disease. Muscle ATP and PCr levels at rest or after exercise did not differ significantly from those of the controls in any patient group. In patients with mitochondrial disease, muscle lactate tended to be lower at rest and increase more during exercise than in controls, the most remarkable rise being measured in patients with adPEO with generalized muscle symptoms and in patients with MELAS point mutation. In McArdle patients, the muscle lactate level decreased during exercise. No correlation was found between the muscle ATP and PCr levels and the respiratory chain enzyme activity.

Topics: Adenosine Triphosphate; Adult; Aged; DNA, Mitochondrial; Electron Transport; Enzymes; Exercise; Exercise Test; Gene Deletion; Genes, Dominant; Genes, Recessive; Glycogen Storage Disease Type V; Humans; Lactic Acid; Male; MELAS Syndrome; Middle Aged; Mitochondrial Myopathies; Muscle, Skeletal; Ophthalmoplegia; Phosphocreatine; Physical Fitness

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)

Topics: Adult; Alanine; Citrates; Citric Acid Cycle; Exercise; Female; Fumarates; Glutamic Acid; Glycogen Storage Disease Type V; Humans; Lactates; Lactic Acid; Malates; Male; Muscle, Skeletal; Phosphocreatine

In McArdle's disease (myophosphorylase deficiency) exercise intolerance is generally attributed to a lack of glycogenolysis, which decreases energy production during exercise. Magnetic resonance imaging data have recently suggested an impairment of the increase in muscle perfusion during exercise in these patients. We have tested this hypothesis by direct measurement of local muscle perfusion increase. Increase in muscle perfusion was assessed by positron emission tomography with oxygen-15 labelled water in five patients with McArdle's disease and five age- and sex-matched healthy volunteers. Radioactivity was measured in both forearms before and after exercise of the right forearm. The exercise intensity was biochemically assessed by in vivo phosphorus-31 magnetic resonance spectroscopy. The estimated increase in muscle perfusion with exercise was 5.7+/-5.5-fold in the patients (range 1.5-12.8) and 22.3+/-12.0-fold in the healthy subjects (range 10.1-37) (P=0.022). The results show a significant impairment of increase in muscle perfusion with exercise in McArdle's disease. Thus patients may suffer not only from a direct lack of glycogenolysis but also from indirectly impaired vasodilation.

Topics: Adult; Female; Forearm; Glycogen Storage Disease Type V; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; Physical Exertion; Tomography, Emission-Computed

A patient with McArdle's syndrome was examined using bicycle ergometry and 31P NMR spectroscopy during exercise. The patients working capacity was approximately half the expected capacity of controls. Muscle energy kinetics improved significantly during intravenous glucose infusion and after 6 weeks of high protein diet. During intravenous infusion of amino acids, no changes in working capacity could be detected. No decrease was seen in intracellular muscle pH during aerobic exercise. A significant decrease in muscle pH during aerobic exercise was detected in all controls.

Topics: Adult; Dietary Proteins; Energy Metabolism; Exercise Test; Glycogen Storage Disease Type V; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Muscle Contraction; Muscles; Phosphates; Phosphocreatine

Static exercise in normal humans causes reflex increases in muscle sympathetic nerve activity (MSNA) that are closely coupled to the contraction-induced decrease in muscle cell pH, an index of glycogen degradation and glycolytic flux. To determine if sympathetic activation is attenuated when muscle glycogenolysis is blocked due to myophosphorylase deficiency (McArdle's disease), an inborn enzymatic defect localized to skeletal muscle, we now have performed microelectrode recordings of MSNA in four patients with McArdle's disease during static handgrip contraction. A level of static handgrip that more than doubled MSNA in normal humans had no effect on MSNA and caused an attenuated rise in blood pressure in the patients with myophosphorylase deficiency. In contrast, two nonexercise sympathetic stimuli, Valsalva's maneuver and cold pressor stimulation, evoked comparably large increases in MSNA in patients and normals. The principal new conclusion is that defective glycogen degradation in human skeletal muscle is associated with a specific reflex impairment in sympathetic activation during static exercise.

Topics: Adenosine Diphosphate; Adult; Glycogen Storage Disease Type V; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Muscles; Phosphates; Phosphocreatine; Phosphorylases; Physical Exertion; Reference Values; Sympathetic Nervous System

In muscle phosphorylase deficiency (McArdle's disease) there is an abnormally rapid fatigue during strenuous exercise. Increasing substrate availability to working muscle can improve exercise tolerance but the effect on muscle energy metabolism has not been studied. Using phosphorus-31 nuclear magnetic resonance (31P-NMR) we examined forearm muscle ATP, phosphocreatine (PCr), inorganic phosphate (Pi) and pH in a McArdle patient (MP) and two healthy subjects (HS) at rest and during intermittent maximal effort handgrip contractions under control conditions (CC) and during intravenous glucose infusion (GI). Under CC, MP gripped to impending forearm muscle contracture in 130 s with a marked decline in muscle PCr and a dramatic elevation in Pi. During GI, MP exercised easily for greater than 420 s at higher tensions and with attenuated PCr depletion and Pi accumulation. In HS, muscle PCr and Pi changed more modestly and were not affected by GI. In MP and HS, ATP changed little or not at all with exercise. The results suggest that alterations in the levels of muscle PCr and Pi but not ATP are involved in the muscle fatigue in McArdle's disease and the improved exercise performance during glucose infusion.

Topics: Adenosine Triphosphate; Adult; Fatigue; Glucose; Glycogen Storage Disease; Glycogen Storage Disease Type V; Humans; Magnetic Resonance Spectroscopy; Male; Muscles; Phosphates; Phosphocreatine; Phosphorus Isotopes

Topical Nuclear Magnetic Resonance (TNMR) is a noninvasive and non-hazardous new technique which allows local observation of chemical composition and metabolism in living objects. This article gives an introduction into TNMR, along with a brief discussion on instrumentation. Some clinically relevant TNMR results from literature will also be described and illustrated with our own experimental spectra of a forearm.

Topics: Adenosine Triphosphate; Energy Metabolism; Glycogen Storage Disease Type V; Glycolysis; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Mitochondria, Muscle; Muscles; Phosphates; Phosphocreatine

Topics: Biopsy; Glycogen Storage Disease Type V; Humans; Hydrogen-Ion Concentration; Infant; Magnetic Resonance Spectroscopy; Muscles; Muscular Diseases; Muscular Dystrophies; Phosphocreatine; Phosphorus

Topics: Adenosine Triphosphate; Adult; Glycogen Storage Disease; Glycogen Storage Disease Type V; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Phosphocreatine; Phosphorus Isotopes; Physical Exertion

Topics: Adenosine Triphosphate; Glycogen Storage Disease Type V; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Phosphates; Phosphocreatine

Topics: Adenosine Triphosphate; Animals; Brain; Glycogen Storage Disease Type V; Humans; Hydrogen-Ion Concentration; Ischemia; Magnetic Resonance Spectroscopy; Metabolism; Muscle Contraction; Muscles; Myocardium; Phosphates; Phosphocreatine; Phosphorus Isotopes