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