Energy to Skeletal Muscles Lecture-1 Glycogen Metabolism
Feb 24, 2016
Energy to Skeletal MusclesLecture-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.
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.
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 ??
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
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
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
Functions of glycogen
LIVER
Sk. Ms
• 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
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
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)
synthesis of glycogen
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)
glycogenlysis
fate of glucose 6-phosphate in liver & skeletal muscles
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
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.)
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.
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.)
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
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
2- Hormonal regulation
hormones affecting glycogen metabolism :
Glucagon: for liver glycogen only
Epinephrine: for liver & muscle glycogen
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
A group of genetic diseases that result from a defect in an enzyme required for glycogen synthesis or
degradation
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
glycogen storage diseases
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
Von Gierke’s Disease
McArdle Syndrome