CBL2

Glycogen Metabolism

Dr. Sanaa Eissa

Prof. of Medical Biochemistry
& Molecular Biology

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 •Describe Glycolytic energy system
•Explain the biochemical basis of McArdle’s dis
•Describe synthesis of glycogen
•Describe glycogenolysis

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 Samir, a 35-year-old man, had a lifelong
history of exercise intolerance that was
often accompanied by episodes of cramping.
He described a sensation of his legs
becoming stiff like a board after walking for
a while; this symptom was relieved by rest
.The episodes were somewhat ameliorated by
drinking sucrose-rich soft drinks immediately
before exercise. Since his childhood, he has
been labeled as “lazy” by family and friends.

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 The latest episode occurred during his first spin
class (stationary bicycling with a resistance
toad) in the Gym. He initially had extreme
weakness in both legs and muscle cramps and
later passed red brown urine.
In subsequent sessions, in addition to the high-
sucrose drink, he reduced the toad on the
bicycle and was able to tolerate the initial phase
of exercise better than before. After resting
for 10-15 minutes, he experienced a "second
wind" and was able to continue his exercise
successfully.
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 Investigations:
•Sensory nerve test conduction showed normal findings.
•Normal blood hemoglobin.
•Serum lactate levels before ischemic exercise test: 8
mg/dL, after test: 8.1 mg/dL.(N: increase more than 50%
of baseline)
•CK: 5,000 IU/L at rest (N: 60-400IU/L), and 35,000 IU/L
with muscle exertion
•LDH : 400 U/L (N:105-230 U/L)
•Serum myoglobin:671 ng/mL (N: 0–85 ng/mL).
•Urine myoglobin: positive (N: negative)
•Fasting blood sugar: 80 mg/dL (N: 70-110)

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 Ischemic exercise test

Normal

McArdle

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 •A muscle biopsy specimen stained for
glycogen showed subsarcolemmal
accumulation of “lakes” of glycogen.
•Histochemical results of enzymes of
glycogen metabolism in muscle biopsy:
1-Myophosphorylase: negative
2-Glycogen synthase: Positive
3-Branching enzyme: Positive
4-UDP-G pyrophosphorylase: Positive
• Genetic testing: homozygous mutation in
PYGM gene diagnostic of McArdle disease

•
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 • Exercise intolerance
(lazy)
Patient’s • Muscle weakness&
complaints cramps
• Red brown urine after
exercise

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 • What are abnormal findings
in patient’s investigations?

•Serum: ­CK, ­ LDH, ­ myoglobin,

Lactate not ­ (post-ischemic ex.test)
•Urine: reddish brown,myoglobin +ve

•Muscle biopsy:­ normal glycogen

•Histochemistry: Myophosphorylase:
Negative

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 What is the diagnosis? Clues?
•
• Symptoms: exercise intolerance, improved by
sucrose soft drink, 2nd wind

• Investigation:Serum: ­CK, ­ LDH, ­ myoglobin,

Lactate not ­ (post-ischemic ex.test)*

• Urine: reddish brown,myoglobin +ve

• Muscle biopsy:­ normal glycogen

• Histochemistery: Myophosphorylase: Negative

• McArdle disease :myophosphorylase deficiency

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 1-What is Glycogen?
It is the storage form of glucose
in all cells mainly in liver& muscle

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 3-What is Glycogen Structure?

Glycogen is a highly branched polymer of

a-glucose units linked together by a-1®4
glycosidic (glucosidic) bond and by a-1®6
glycosidic bonds at the branching points.

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 1

5
1 4

Formation of glycosidic bonds between 2 glucose

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 Biological Importance of Branching

2 • Increases no. of branches ends to be

extended in glycogen synthesis

3 • Increases the sites of breaking attacks by

phosphorylase in glycogenolysis

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 Pyrophosphorylase: releases pyrophosphate=
PPi= 2 linked phosphates

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 Glycogenin initiates glycogen synthesis.
Glycogenin is a protein that catalyzes attachment of a
glucose molecule to one of its own tyrosine residues.

Tyr- active site

active site -Tyr

Glycogenin dimer

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 6 CH
2OH
UDP-glucose tyrosine residue
H
5 O H of Glycogenin
H O O C O
4 OH H 1
OH O P O P O Uridine HO C CH
3 2 H2
H OH O- O- NH

6 CH
2OH
O-linked 5 O
glucose H H
H
C O
residue 4 OH H 1
OH O C CH + UDP
3 2 H2
H OH NH

CH2OH CH2OH
A glycosidic
H O H
bond
H
is formed
O H between the C1 of
theOH
H glucose moietyHderived from UDP-glucose
H OH H
C O and

the hydroxyl Ooxygen of a tyrosine

OH O side-chain
C CH of
OH . UDP is Hreleased.
H2
Glycogenin
H OH NH
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 18
Essentials of Medical Biochemistry, With Clinical Cases,2011, Pages 151-168
 Glycogen synthase

It is a key regulatory enzyme in glycogen synthesis

(glycogenesis)

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 Glycogenin ( protein core)

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 What is myophosphorylase?

It is a key regulatory enzyme in glycogen breakdown

(glycogenolysis)

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 Glycogenolysis

PLP

Debranching
Debranching

Debranching

It is not the reversal of glycogenesis

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 What is the significance of Glycogen?
Relation to type of Ms.excercise

Muscle contains 1-2% of its weight as a

fuel for anaerobic glycolysis during
contraction.
• Liver contains 7-10% of its weight for
maintainance of blood glucose during
short fast

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 Explain normal fasting blood glucose in
this patient

Ms Liver
Hepatic-
Myophosphorylase phosphorylase

Muscle- Hepatic-
Glycogenolysis Glycogenolysis

Muscle-disease Low bl.glucose

Normal bl.glucose Normal muscle

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 Case Analysis?

Muscle phosphorylase deficiency→ ¯ ATP

Exercise intolerance& cramps

¯ATP→ dysfunction in Na+/K+ ATPase, Ca+2 ATPase

­I.C. Na+&Ca+2 ­I.C.H2O→ swelling →rupture of myocytes

Release of LDH, CK, myoglobin to blood

Myoglobinuria Reddish brown urine

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 Case Analysis?

No glycogenolysis→

Accumulation of normal glycogen in muscle

No anaerobic glycolysis from glycogen

No ­ in lactate after forearm exercise ischemic test

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 Case Analysis?

Sucrose soft drink before excercise→¯ symptoms

Supply glucose Glycolysis

After 10-15 mins →2nd wind

Aerobic oxidation works on

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 What is the relation between PGYM mutation and
the disease?

• Autosomal recessive 1:100,000 USA

• 147 pathogenic mutations have been reported.
• Exon 1 and 17 are mutational hot-spots in
PYGM
• 50% of the described mutations are
missense.

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 Suggest a possible molecular-based therapy ?

Gene replacement
therapy or Gene
editing

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 Thank You
Assignment
Dietary sources of creatine
Many athletes take creatine supplements.
Why do you think they do this?
What sort of sports would this be an advantage
in?

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