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Energy to Skeletal Muscles Lecture-1 Glycogen Metabolism

Energy to Skeletal Muscles Lecture-1 Glycogen Metabolism. Objectives. 1- The concept of storing excess energy (mainly from glucose) in certain body cells including skeletal muscle cells in the form of glycogen.

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Energy to Skeletal Muscles Lecture-1 Glycogen Metabolism

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  1. Energy to Skeletal MusclesLecture-1Glycogen Metabolism

  2. 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.

  3. When glucose is essential? A constant source ofGLUCOSEis 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) So, it is essential to have a continuous supply for glucose 24 hours, 7 days (724 !!) BUT HOW ??

  4. Sources of glucose to human body Glucose can be obtained from three primary sources: • Carbohydrate DIET: - sporadic - depends on the diet (nature & amount) - is notalways 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

  5. Glycogen locations 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)

  6. Functions of glycogen Function of muscleglycogen: 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

  7. Functions of glycogen LIVER Sk. Ms

  8. Structure of glycogen • 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

  9. Metabolism of glycogen Glycogen synthesis (Glycogenesis) Synthesis of Glycogen from Glucose a mechanism tostore glucose in Liver & Skeletal Muscles Glycogen degradation (Glycogenlysis) Breakdown of Glycogen to Glucose Liver glycogen givesblood glucose Skeletal Muscleglycogen givesenergy to skeletal muscles

  10. Glycogenesis(synthesis of glycogen in liver & skeletal muscles) 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 fora1-4 link synthesis UDP-glucose as a building block 4- Branching of glycogen by branching enzyme for a1-6 link synthesis

  11. synthesis of glycogen

  12. Glycogenlysis(breakdown of glycogen in liver & skeletal muscles) 1- Shortening of glycogen chain : byglycogen phosphorylase Cleaving ofa(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 : bydebranching enzymes Cleaving ofa(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 notconverted to free glucose (noglucose 6-phosphatase) - So, it is nottransported to blood - BUT: it is used only as a source of energy inside sk. muscles (by glycolysis that yields lactic acid)

  13. glycogenlysis

  14. fate of glucose 6-phosphate in liver & skeletal muscles

  15. Regulation of glycogen metabolism in skeletal muscles Synthesis & degradation of glycogen are tightly regulated Glycogen synthesisbegins when the muscle is at rest Glycogen degradationoccurs during active exercise

  16. Regulation of glycogen metabolism in skeletal muscles (cont.) Regulation of glycogen metabolism(cont.) Regulation of glycogen metabolism is accomplished on two levels: 1- Within individual cells of skeletal muscles(allostericregulation) 2- Allover the body (hormonalregulation)

  17. 1- Regulation within individual cells of sk.ms. 1- Regulation in the well-fed state: in well-fed state glucose 6-phosphate& ATP are increased • Glycogen synthaseis allosterically ACTIVATEDby: G-6-P • Glycogen phosphorylaseis allosterically INHIBITEDby : G-6-P& ATP

  18. 1- Regulation within individual cells of sk.ms. (cont.) 2- During muscular contraction: During muscular contraction calcium& AMPare increased Glycogen phosphorylaseis ACTIVATEDby calcium & AMP

  19. 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

  20. Summary of regulation within individual cells 1- in well-fed state: G 6-P& ATP stimulationof synthase synthesis inhibition of phosphorylase degradation 2- In muscular contraction: Ca2+ & AMP stimulation of phosphorylase degradation

  21. 2-Hormonal regulation hormones affecting glycogen metabolism : Glucagon: for liver glycogen only Epinephrine: for liver & muscle glycogen

  22. Hormonal Regulation by Epinephrine Muscle contraction Epinephrine release In Skeletal muscle: Epinephrine/receptor binding Second messenger: cAMP Response: Enzyme phosphorylation P P Glycogen phosphorylase (Active form) Stimulation of glycogenolysis Glycogen synthase (Inactive form) Inhibition of glycogen synthesis

  23. glycogen storage diseases A group of genetic diseases that result from a defect in an enzyme required for glycogen synthesis or degradation

  24. glycogen storage diseases • 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

  25. 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

  26. Von Gierke’s Disease

  27. McArdle Syndrome

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