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McArdle's disease-muscle glycogen phosphorylase deficiency
Transcript of McArdle's disease-muscle glycogen phosphorylase deficiency
muscle glycogen phosphorylase deficiency
By:Amir & Pedro 1.2. Identification of the enzyme defect 1.3. Glycogen phosphorylase 2. Clinical presentation in McArdle's disease
3. Glycogen utilisation in skeletal muscle 4.Clinical management and therapy Clinical presentation
symptomatoloy the addition of crystalline phosphorylase to a muscle homogenate from an affected individual resulted in a 3-fold increase in lactate production, whereas no lactate was generated in the absence of exogenous phosphorylase . McArdle's disease was thus identified as a lack of muscle glycogen phosphorylase. It has subsequently been classified as Glycogen Storage Disease Type V catalyses the phosphorolytic cleavage of glycogen to glucose-l-phosphate at a-l, 4-glycosidic linkages. This glucose-l-phosphate enters the glycolytic pathway to generate ATP with the concomitant formation of pyruvate or lactate. debrancher enzyme, is required for the cleavage of a-1, 6-glycosidic linkages which form the branch points 4.1.Exercise management(Weight determines oxygen consumption during walking,) I. Introduction 2. Clinical presentation in McArdle's disease . 3. Glycogen utilisation in skeletal muscle 4.Clinical management and therapy In a 1951 paper in the journal Clinical Science Brian McArdle described a 30 year old man experiencing pain followed by weakness and stiffness after exercise. this patient failed to produce a rise in blood lactate in response to ischaemic forearm exercise. This suggested that there was a block in the glycolytic pathway preventing the breakdown of glycogen to lactate Isozymic forms of glycogen phosphorylase Glycogen phosphorylase has three isozymic forms: these are known as the muscle, liver and brain isozymes. both the amino acid and nucleotide sequences of the muscle and brain forms show greater similarity to each other than to the liver sequences. The muscle isozyme provides ATP for muscle contraction whereas the liver form has a homeostatic function in the regulation of glucose release from hepatic glycogen stores. The brain isozyme is thought to provide an emergency supply of glucose during periods of anoxia or hypoglycaemia Activation of muscle glycogen phosphorylase There are two forms of glycogen phosphorylase phosphorylase a (higher activity) phosphorylase b (lower activity) Phosphorylation of the muscle isozyme is under neural and hormonal control !! . Neural control mediated by calcium flux via calmodulin (Calcium ions released from the sarcoplasmic reticulum, upon initiation of muscle contraction,bind to the calmodulin y-subunit of phosphorylase kinase thus activating it. This enzyme phosphorylates glycogen phosphorylase resulting in more of the high-activited phosphorylase a and hence, glycogen breakdown is induced) Hormonal control mediated via the glycogenolytic cascade in response to adrenaline which activates the cAMP-dependent protein kinase. This enzyme activates phosphorylase kinase by phosphorylation and this in turn results in an increase in phosphorylase a. Each subunit of the phosphorylase dimer binds, in a tight complex, one molecule of the cofactor pyridoxal-5'phosphate  to an active site lysine residue via a Schiff base. Glycogen storage disease type V McArdel’s disease Myalgia
Early fatigue and muscle weakness (exercise)
Most affected by high intensity exercise or short duration.
Less intense but sustained activity.
If exercise continues once pain occurs, then myoglobinuria may result. Patiens frequently find that they can continue exercise with and increased endurance if they rest briefly at the first sings of muscle pain.
This is attributed to either a shift in a metabolic pathway or a circulatory adjustment. The «second wind» phenomenon
A very mild form of the symptoms : excessive tiredness and poor stamina
Late onset form of the disease >40 years which not exercise-induced symptoms were noted previously.
Fatal infantile form with progressive weakness soon after birth and severe breathing dificulties followed by death before 4 months ( 2 sisters).
Exercise-induced myoglobinuria in an 8 years patient (no previous exercise intolerance).
Second episode of renal failure in a patient. Clinical heterogeneity Diagnosed by negative histochemical staining for phosphorylase activitz in a muscle biopsy.
Low levels of phosphorylase activity result in a deep blue stain, in the absence the section remains brown.
McArdel’s patient often show subsarcolemmal deposits of glycogen detected with acis-Schiff(PAS) stain (3-5 times glycogen content of normal individuals). Histology and the diagnosis Ischaemic forearm test: based on the failure of muscle to produce blood lactate levels to rise in response to exercise. (not especific for glycogen phopho.)
Cell damage due to over-exertion of the muscle, realising intracellular components into circulation like myoglobin.
Creatine kinase activity rise.
Leakage of potassium because of muscle damage.
More fatigable patients by electrical stimulation. Exercise analysis In resting state, fatty acid oxidation predominates in skeletal muscle in normal individuals.
But during exercise, the energy requirements are largely met by glycogen breakdown and anaerobic glycolysis.
Aerobic oxidation limited during intense exercise because circulation cannot provide substrates and oxigen quickly enough to meet energy demands. Glycogen utilization during exercise Muscle glycogen phosphorylase breaks down it to glucose-1-phosphate to generate ATP (glycolitic path) whith formation of pyruvate and under anaerobic conditions lactate.
Glycogen for glycolysis instead of intracellular glucose results in greater net ATP generation and delays muscle fatigue Glycogen utilization during exercise McArdel’s patients cannot mobilise their muscle glycogen storages. Depletion of ATP and glucose in few mins (onset of symptons).
Impaired oxidative phosphorilation because of the low sustrate flux, low Acetyl-CoA formation.
Acetyl-Coa regenerated from fatty acid oxidation( limited to only well trained people). Correlation of symptomatology with an absence of glycogen phosporylase This decline in oxiation Phosphorylation results ind decreased oxygen uptake in muscle 30-50% of normal values.
In adition patients exhibit a disproportionate increase in heart rate and ventilation compare to normal individuals. Correlation of symptomatology with an absence of glycogen phosporylase Absence of glycolysis and reduction of phosphorylation in patiens means that:
Increased reliance on creatine kinase and adenylate kinase reactions. Both to regenerated ATP rapidly to provide an inmediate short-term source of energy.
The action of these enzymes in combination with decreased ATP generation from carbohydrate adn fatty acids results in increased levels of ADP and AMP within the muscle, affecting normal metabolism of adenine nucleotides. Other biochemical effects of the glycogen block In adtion McArdles patien show enhanced response to hormones compare to normal individuals ,growth hormone, cortisol, noradrenaline etc which result in movilisation of extramuscular fuel, such as glucose and free fatty acids to meet energy requeriments. Other biochemical effects of the glycogen block 4.2.Dietary management A:Carbohydrate supplementation B:Fatty acid supplementation C:Vitamin B-6 supplementation D:Amino acid/protein supplementation in McArdle's disease,the supply of precursors for alanine and glutamine is compromised. In exercising McArdle's muscle, glycolytic flux is suppressed. a decreased ability to remove ammonia, in the form of alanine and glutamine might explain the elevated plasma ammonia levels during exercise in McArdle's disease. These increased ammonia levels may be responsible in part for the muscle pain and fatigue Release of alanine from exercising McArdle's muscle peaks earlier,and total alanine output is lower than in normal individuals. This is consistent with an initially increased demand on pyruvate for transamination and a subsequent decrease in the pyruvate pool which cannot be However, the magnitude of alanine uptake into muscle is substantially lower than initial release.
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