Breakdown of adenine nucleotide pool in fatiguing skeletal muscle in McArdle's disease: A noninvasive31P-MRS and EMG study

2003 ◽  
Vol 27 (6) ◽  
pp. 728-736 ◽  
Author(s):  
Jochen Zange ◽  
Torsten Grehl ◽  
Catherine Disselhorst-Klug ◽  
Günter Rau ◽  
Klaus Müller ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adenine Nucleotide ◽  
Mcardle's Disease ◽  
Mcardle’S Disease ◽  
Adenine Nucleotide Pool

Purine metabolic pathways in rat hindlimb perfusion model during ischemia and reperfusion

1993 ◽  
Vol 265 (4) ◽  
pp. H1074-H1081 ◽  
Author(s):  
B. Soussi ◽  
K. Lagerwall ◽  
J. P. Idstrom ◽  
T. Schersten
Keyword(s):  
Skeletal Muscle ◽  
Blood Cell ◽  
Xanthine Oxidase ◽  
Flow Rate ◽  
Adenine Nucleotide ◽  
Vascular Endothelial Cell ◽  
Nucleotide Metabolism ◽  
Computer Simulation Model ◽  
Tissue Homogenates ◽  
Adenine Nucleotide Pool

The perfused rat hindlimb preparation was used with a blood cell-free perfusate to investigate alterations in the purine nucleotide metabolism, flow rate, perfusion pressure, and venous excretion in response to ischemia and ischemia followed by reperfusion in skeletal muscle. The development of a physical hindrance during postischemic reperfusion, indicated by an increase in reperfusion pressure and a decrease in flow rate, coincided with a 90% decrease in phosphocreatine and a 50-70% reduction in total adenine nucleotide pool. The reflow impairment could not be explained by blood cell plugging of the capillaries. Washout of several metabolites was demonstrated during reperfusion. Hypoxanthine accumulated intracellularly during ischemia, and a substantial amount of uric acid was excreted into the venous effluent during reperfusion. The experimental data were fitted into a computer simulation model of the purine pathways. The model indicated that AMP deaminase was the predominant enzymatic pathway for the AMP degradation. It was demonstrated that ATP preferably accumulated as inosine-5'-monophosphate during ischemia and that xanthine oxidase was undetectable in skeletal muscle tissue homogenates. However, vascular endothelial cell xanthine oxidase activity responsible for a free radical-induced reperfusion injury could not be excluded.

Skeletal muscle myosin heavy chain isoforms and energy metabolism after clenbuterol treatment in the rat

2000 ◽  
Vol 279 (3) ◽  
pp. R1076-R1081 ◽  
Author(s):  
P. Rajab ◽  
J. Fox ◽  
S. Riaz ◽  
D. Tomlinson ◽  
D. Ball ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Myosin Heavy Chain ◽  
Body Mass ◽  
Heavy Chain ◽  
Adenine Nucleotide ◽  
Prolonged Treatment ◽  
Skeletal Muscle Myosin ◽  
Adenine Nucleotide Pool ◽  
Muscle Myosin

Prolonged treatment with the β2-adrenoceptor agonist clenbuterol (1–2 mg · kg body mass−1 · day −1) is known to induce the hypertrophy of fast-contracting fibers and the conversion of slow- to fast-contracting fibers. We investigated the effects of administering a lower dose of clenbuterol (250 μg · kg body mass−1 · day−1) on skeletal muscle myosin heavy chain (MyHC) protein isoform content and adenine nucleotide (ATP, ADP, and AMP) concentrations. Male Wistar rats were administered clenbuterol ( n = 8) or saline ( n = 6) subcutaneously for 8 wk, after which the extensor digitorum longus (EDL) and soleus muscles were removed. We demonstrated an increase of type IIa MyHC protein content in the soleus from ∼0.5% in controls to ∼18% after clenbuterol treatment ( P < 0.05), which was accompanied by an increase in the total adenine nucleotide pool (TAN; ∼19%, P < 0.05) and energy charge [E-C = (ATP + 0.5 ADP)/(ATP + ADP + AMP); ∼4%; P < 0.05]. In the EDL, a reduction in the content of the less prevalent type I MyHC protein from ∼3% in controls to 0% after clenbuterol treatment ( P < 0.05) occurred without any alterations in TAN and E-C. These findings demonstrate that the phenotypic changes previously observed in slow muscle after clenbuterol administration at 1–2 mg · kg body mass−1 · day−1 are also observed at a substantially lower dose and are paralleled by concomitant changes in cellular energy metabolism.

The pathophysiology of McArdle's disease: clues to regulation in exercise and fatigue

1986 ◽  
Vol 61 (2) ◽  
pp. 391-401 ◽  
Author(s):  
S. F. Lewis ◽  
R. G. Haller
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fatigue ◽  
Muscle Afferents ◽  
Common Denominator ◽  
Circulatory Response ◽  
Mcardle's Disease ◽  
O2 Transport ◽  
Mcardle’S Disease ◽  
Muscle Phosphorylase ◽  
Response To Exercise

Muscle phosphorylase deficiency (McArdle's disease) has conventionally been considered a disorder of glycogenolysis, and the associated impairment in oxidative metabolism has been largely overlooked. Muscle glycogen normally is the primary oxidative fuel at exercise work loads requiring more than 75–80% of maximal O2 uptake (VO2max). Evidence is presented to support the hypothesis that a limited flux through the Embden-Myerhof pathway in McArdle's disease reduces the capacity to generate NADH required to support a normal VO2max. The extent of the oxidative defect is substrate dependent; i.e., it can be partially corrected by increasing the availability of alternative oxidative substrates (e.g., glucose, free fatty acids) to working muscle. Experiments employing modification of substrate availability closely link the hyperkinetic circulatory response to exercise (i.e., an abnormally large increase in O2 transport to skeletal muscle) and the premature muscle fatigue and cramping of McArdle patients with their oxidative impairment and suggest that a metabolic common denominator in these abnormal responses may be a pronounced decline in the muscle phosphorylation potential ([ATP]/[ADP][Pi]). The hyperkinetic circulation likely is mediated by the local effects on metabolically sensitive skeletal muscle afferents and vascular smooth muscle of K+, Pi, or adenosine or a combination of these substances released excessively from working skeletal muscle. The premature muscle fatigue and cramping of McArdle patients does not appear to be due to depletion of ATP but is associated with an increased accumulation of Pi and probably ADP in skeletal muscle. Accumulations of Pi and ADP are known to inhibit the myofibrillar, Ca2+, and Na+-K+-ATPase reactions.

Metabolic control of cardiac output response to exercise in McArdle's disease

1984 ◽  
Vol 57 (6) ◽  
pp. 1749-1753 ◽  
Author(s):  
S. F. Lewis ◽  
R. G. Haller ◽  
J. D. Cook ◽  
C. G. Blomqvist
Keyword(s):  
Skeletal Muscle ◽  
Cardiac Output ◽  
Nicotinic Acid ◽  
Plasma Free Fatty Acid ◽  
Muscle Afferents ◽  
Tight Coupling ◽  
Metabolic State ◽  
Mcardle's Disease ◽  
O2 Transport ◽  
Mcardle’S Disease

During dynamic exercise cardiac output (Q) normally increases approximately 5 liters per liter of increase in O2 uptake (Vo2) (i.e., delta Q/delta Vo2 approximately equal to 5), indicative of a tight coupling between systemic O2 transport and utilization. We studied four patients with muscle phosphorylase deficiency (McArdle's disease) in whom Q was normal at rest, but delta Q/delta Vo2 was 14.1 +/- 1.3 during bicycle exercise. Procedures designed to alter the availability of substrates were employed to test the hypothesis that the increased delta Q/delta Vo2 is linked to the abnormal metabolic state of skeletal muscle. Fasting plus prolonged moderate exercise was used to increase the availability of plasma free fatty acid (FFA) and resulted in a normalization of delta Q/delta Vo2 (5.3 +/- 0.4). Hyperglycemia (70% above control levels) partially normalized delta Q/delta Vo2. Nicotinic acid lowered plasma FFA concentration and dramatically increased delta Q/delta Vo2 (4.6 to 13.7) when administered after fasting plus prolonged exercise in one patient. Glucose infusion after nicotinic acid administration markedly lowered delta Q/delta Vo2. The results support the hypothesis and suggest that the metabolic state of skeletal muscle, possibly via activation of muscle afferents, participates in the regulation of systemic O2 transport.

Impaired oxidative metabolism increases adenine nucleotide breakdown in McArdle's disease

1990 ◽  
Vol 69 (4) ◽  
pp. 1231-1235 ◽  
Author(s):  
K. Sahlin ◽  
N. H. Areskog ◽  
R. G. Haller ◽  
K. G. Henriksson ◽  
L. Jorfeldt ◽  
...  
Keyword(s):  
Heart Rate ◽  
Healthy Subjects ◽  
Adenine Nucleotide ◽  
Tricarboxylic Acid Cycle ◽  
Work Load ◽  
Maximal Heart Rate ◽  
Mcardle's Disease ◽  
Mcardle’S Disease ◽  
Arterial Plasma ◽  
Lactate Levels

Two patients with muscle phosphorylase deficiency [McArdle's disease (McA)] were studied during bicycle exercise at 40 (n = 2) and 60 W (n = 1). Peak heart rate was 170 and 162 beats/min, corresponding to approximately 90% of estimated maximal heart rate. Muscle samples were taken at rest and immediately after exercise from the quadriceps femoris. Lactate content remained low in both muscle and blood. Acetylcarnitine, which constitutes a readily available form of acetyl units and thus a substrate for the tricarboxylic acid cycle, was very low in McA patients both at rest and during exercise, corresponding to approximately 17 and 11%, respectively, of that in healthy subjects. Muscle NADH was unchanged during exercise in McA patients in contrast to healthy subjects, in whom NADH increases markedly at high exercise intensities. Despite low lactate levels, arterial plasma NH3 and muscle inosine 5'-monophosphate increased more steeply relative to work load in McA patients than in healthy subjects. The low postexercise levels of lactate, acetylcarnitine, and NADH in McA patients support the idea that exercise performance is limited by the availability of oxidative fuels. Increases in muscle inosine 5'-monophosphate and plasma NH3 indicate that lack of glycogen as an oxidative fuel is associated with adenine nucleotide breakdown and increased deamination of AMP. It is suggested that the early onset of fatigue in McA patients is caused by an insufficient rate of ADP phosphorylation, resulting in transient increases in ADP.

Decreased insulin action in skeletal muscle from patients with McArdle's disease

2002 ◽  
Vol 282 (6) ◽  
pp. E1267-E1275 ◽  
Author(s):  
Jakob N. Nielsen ◽  
John Vissing ◽  
Jørgen F. P. Wojtaszewski ◽  
Ronald G. Haller ◽  
Najma Begum ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Tolerance ◽  
Muscle Glycogen ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Oral Glucose ◽  
Mcardle's Disease ◽  
Mcardle’S Disease ◽  
The Difference ◽  
Glycogen Synthase Activity

Insulin action is decreased by high muscle glycogen concentrations in skeletal muscle. Patients with McArdle's disease have chronic high muscle glycogen levels and might therefore be at risk of developing insulin resistance. In this study, six patients with McArdle's disease and six matched control subjects were subjected to an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp. The muscle glycogen concentration was 103 ± 45% higher in McArdle patients than in controls. Four of six McArdle patients, but none of the controls, had impaired glucose tolerance. The insulin-stimulated glucose utilization and the insulin-stimulated increase in glycogen synthase activity during the clamp were significantly lower in the patients than in controls (51.3 ± 6.0 vs. 72.6 ± 13.1 μmol · min−1 · kg lean body mass−1, P < 0.05, and 53 ± 15 vs. 79 ± 9%, P < 0.05, n = 6, respectively). The difference in insulin-stimulated glycogen synthase activity between the pairs was significantly correlated ( r = 0.96, P < 0.002) with the difference in muscle glycogen level. The insulin-stimulated increase in Akt phosphorylation was smaller in the McArdle patients than in controls (45 ± 13 vs. 76 ± 13%, P < 0.05, respectively), whereas basal and insulin-stimulated glycogen synthase kinase 3α and protein phosphatase-1 activities were similar in the two groups. Furthermore, the ability of insulin to decrease and increase fat and carbohydrate oxidation, respectively, was blunted in the patients. In conclusion, these data show that patients with McArdle's glycogen storage disease are insulin resistant in terms of glucose uptake, glycogen synthase activation, and alterations in fuel oxidation. The data further suggest that skeletal muscle glycogen levels play an important role in the regulation of insulin-stimulated glycogen synthase activity.

What can metabolic myopathies teach us about exercise physiology?

2006 ◽  
Vol 31 (1) ◽  
pp. 21-30 ◽  
Author(s):  
Mark A Tarnopolsky
Keyword(s):  
Skeletal Muscle ◽  
Aerobic Capacity ◽  
Human Skeletal Muscle ◽  
Exercise Physiology ◽  
Maximal Aerobic Capacity ◽  
Nutritional Interventions ◽  
Mcardle's Disease ◽  
Metabolic Myopathies ◽  
Myoadenylate Deaminase ◽  
Mcardle’S Disease

Exercise physiologists are interested in metabolic myopathies because they demonstrate how knocking out a component of a specific biochemical pathway can alter cellular metabolism. McArdle's disease (myophosphorylase deficiency) has often been studied in exercise physiology to demonstrate the influence of removing the major anaerobic energy supply to skeletal muscle. Studies of patients with McArdle's disease have shown the increased reliance on blood-borne fuels, the importance of glycogen to maximal aerobic capacity, and the use of nutritional strategies to bypass metabolic defects. Myoadenylate deaminase deficiency is the most common metabolic enzyme deficiency in human skeletal muscle. It is usually compensated for endogenously and does not have a major influence on high-energy power output. Nutritional interventions such as carbohydrate loading and carbohydrate supplementation during exercise are essential components of therapy for patients with fatty acid oxidation defects. Cases of mitochondrial myopathies illustrate the importance of peripheral oxygen extraction for maximal aerobic capacity and show how both exercise and nutritional interventions can partially compensate for these mutations. In summary, metabolic myopathies provide important insights into regulatory and nutritional aspects of the major biochemical pathways of intermediary metabolism in human skeletal muscle. Key words: myoadenylate deaminase deficiency, MELAS syndrome, McArdle's disease, mitochondrial disease, inborn errors of metabolism.

Cytosolic pH buffering during exercise and recovery in skeletal muscle of patients with McArdle’s disease

2008 ◽  
Vol 105 (5) ◽  
pp. 687-694 ◽  
Author(s):  
Graham J. Kemp ◽  
Caterina Tonon ◽  
Emil Malucelli ◽  
Claudia Testa ◽  
Alexandra Liava ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cytosolic Ph ◽  
Ph Buffering ◽  
Mcardle's Disease ◽  
Mcardle’S Disease
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