Energy to Skeletal Muscles Lecture-1 Glycogen Metabolism
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Transcript of Energy to Skeletal Muscles Lecture-1 Glycogen Metabolism
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Energy to Skeletal MusclesLecture-1
Glycogen Metabolism
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Objectives
1- The concept of storing excess energy (mainly from glucose) in certain body cells including skeletal muscle cells in the form of glycogen.
2- Main lines of glycogen metabolism & its biological importance especially in muscular exercise.
3- Importance of studying glycogen structure & metabolism in verifying glycogen storage diseases including their clinical applications.
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A constant source of GLUCOSE is an absolute requirement for human life as it is:
1- Preferred energy of the brain
2- Required energy source for cells with no or few mitochondria
(for anaerobic glycolysis in RBCs)
3- Essential source of energy for exercising muscle (for anaerobic glycolysis in skeletal muscles)
When glucose is essential?
So, it is essential to have a continuous supply for glucose 24 hours, 7 days (724 !!)BUT HOW ??
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Sources of glucose to human body
Glucose can be obtained from three primary sources:
• Carbohydrate DIET : - sporadic - depends on the diet (nature & amount) - is not always a reliable source of glucose
• GLYCOGEN DEGRADATION (glycogenlysis from glycogen stores)
• GLUCONEOGENESIS (synthesis of glucose from non carbohydrate sources)
- can provide sustained synthesis of glucose - BUT: slow in responding to blood glucose falling
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Glycogen is available in cytosol of skeletal muscle & liver 400 gram in muscles (1-2% of resting muscles weight)
100 grams in liver (~ 10% of well-fed liver)
Glycogen locations
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Functions of glycogen
Function of muscle glycogen: Source of glucose (fuel for generating ATP) during muscular
exercise
Function of liver glycogen:
a source for blood glucose (for all cells of the body) during early stages of fasting
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Functions of glycogen
LIVER
Sk. Ms
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• Glycogen is a branched chain polysaccharide made from a- D-glucose.• Glucose molecules are bound by a(1 - 4) bond• Branches are linked by a(1 - 6) bond
Structure of glycogen
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Glycogen synthesis (Glycogenesis) Synthesis of Glycogen from Glucose
a mechanism to store glucose in Liver & Skeletal Muscles
Glycogen degradation (Glycogenlysis)Breakdown of Glycogen to Glucose
Liver glycogen gives blood glucose Skeletal Muscle glycogen gives energy to skeletal muscles
•
Metabolism of glycogen
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Steps of glycogen synthesis in cytosol of liver & skeletal muscles (in brief)
1- UDP-glucose Synthesis from glucose (using UTP): UDP glucose is the building block for glycogen synthesis
2- Primer : on which glycogen is synthesized Primer is either: - glycogen fragment or: - glycogenin (in absence of glycogen fragment) 3- Elongation of a primer: by glycogen synthase for a1-4 link synthesis UDP-glucose as a building block
4- Branching of glycogen by branching enzyme for a1-6 link synthesis
Glycogenesis (synthesis of glycogen in liver & skeletal muscles)
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synthesis of glycogen
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Glycogenlysis(breakdown of glycogen in liver & skeletal muscles)
1- Shortening of glycogen chain : by glycogen phosphorylase Cleaving of a(1-4) bond of the glycogen chain producing glucose 1-phosphate molecules Glucose 1-phosphate is converted to glucose 6-phosphate (by mutase enzyme)
2- Removal of branches : by debranching enzymes Cleaving of a(1-6) bond of the glycogen chain producing few free glucose molecules
3- Fate of glucose 6-phosphate
In liver: - G-6P is converted to free glucose (by glucose 6-phosphatase- only available in liver) - Free Glucose is transported to blood (blood glucose)
In skeletal muscles:
- G-6P is not converted to free glucose (no glucose 6-phosphatase) - So, it is not transported to blood - BUT: it is used only as a source of energy inside sk. muscles (by glycolysis that yields lactic acid)
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glycogenlysis
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fate of glucose 6-phosphate in liver & skeletal muscles
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Synthesis & degradation of glycogen are tightly regulated
Glycogen synthesis begins when the muscle is at rest
Glycogen degradation occurs during active exercise
Regulation of glycogen metabolism in skeletal muscles
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Regulation of glycogen metabolism is accomplished on two levels:
1- Within individual cells of skeletal muscles(allosteric regulation)
2- Allover the body (hormonal regulation)
Regulation of glycogen metabolism(cont.)Regulation of glycogen metabolism
in skeletal muscles (cont.)
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1- Regulation in the well-fed state: in well-fed state glucose 6-phosphate & ATP are increased
• Glycogen synthase is allosterically ACTIVATED by:
G-6-P
• Glycogen phosphorylase is allosterically INHIBITED by :
G-6-P & ATP
1- Regulation within individual cells of sk.ms.
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2- During muscular contraction:
During muscular contraction calcium & AMP are increased
Glycogen phosphorylase is ACTIVATED by calcium & AMP
1- Regulation within individual cells of sk.ms. (cont.)
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Calcium effect on muscle glycogen metabolism
Increase of calcium during muscle contraction
Formation of Ca2+ -calmodulin complex
Activation of Ca2+ -dependent enzymes e.g. glycogen phosphorylase
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Summary of regulation within individual cells
1- in well-fed state:
G 6-P & ATP stimulation of synthase synthesis inhibition of phosphorylase degradation
2- In muscular contraction:
Ca2+ & AMP
stimulation of phosphorylase degradation
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2- Hormonal regulation
hormones affecting glycogen metabolism :
Glucagon: for liver glycogen only
Epinephrine: for liver & muscle glycogen
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Hormonal Regulation by Epinephrine
Muscle contractionEpinephrine release
In Skeletal muscle: Epinephrine/receptor bindingSecond messenger: cAMP
Response: Enzyme phosphorylation
Glycogen synthase(Inactive form)
Inhibition of glycogen synthesis
Glycogen phosphorylase(Active form)
Stimulation of glycogenolysis
PP
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A group of genetic diseases that result from a defect in an enzyme required for glycogen synthesis or
degradation
glycogen storage diseases
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• GSD Ia (Von Geirk disease) & Ib Glucose 6-phosphatase deficiency
• GSD II (Pompe’s disease) Failure to lysosomal breakdown of glycogen (1-4 glucosidase def.) • GSD III (Cori disease) Deficiency of debranching enzyme (for 1-6 link removal in glycogenlysis)
• GSD IV (Andreson’s disease) Deficiency of branching enzyme (of glycogen synthesis)
• GSD V (Mc Ardle’ disease) Deficiency of glycogen phosphorylase (of glycogenlysis)
• GSD VI (hepatic phosphorylase deficiency) Deficiency of glycogen phosphorylase (of glycogenlysis)
• GSD VII Deficiency of phosphofructokinase
glycogen storage diseases
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Von Gierke’s Disease
• Caused by deficiency in glucose 6-phosphatase• Glucose 6-phosphate is trapped inside liver cells• No glucose is transported to blood from glycogenlysis
Clinical Manifestations:
• Hypoglycemia: due to impaired glucose release from cells of liver
• Hepatomegaly: due to accumulation of glycogen in the liver • Hyperuricaemia (and Gout): due to increased metabolism of G-6-P via pentose phosphate pathway, forming ribose 5-phosphate --- purines ---- uric acid
• Hyperlactemia & Metabolic (lactic) Acidosis
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Von Gierke’s Disease
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McArdle Syndrome