Download Creatine Metabolism

Energy to Skeletal Muscles
Lecture-2
Creatine Metabolism
Objectives
• To study the importance of creatine in muscle as a
storage form of energy
• To understand the biosynthesis of creatine
• To study the process of creatine degradation and
formation of creatinine as an end product
• To understand the clinical importance of creatinine as
a sensitive indicator of kidney function
• To study different types of creatine kinase (CK) and
their clinical importance
Overview
Phosphagen is an energy-rich
phosphate compound.
Breakdown of a phosphagen
such as creatine phosphate
enables ATP (adenosine
triphosphate) to be generated
very quickly without oxygen.
ATP is the only chemical energy
which can be used directly by
contracting muscles.
Creatine Biosynthesis
Three amino acids are required:
Glycine
Arginine
Methionine (as S-adenosylmethionine)
Site of biosynthesis:
Step 1: Kidneys
Step 2: Liver
Creatine Biosynthesis
Arginine
Kidneys
+
Glycine
Amidinotransferase
Ornithine
Guanidinoacetate
Liver
SAM
Methyltransferase
SAH
Creatine
Distribution of body creatine
• From liver, transported to other tissues
• 98% of creatine are present in skeletal & heart muscles
• In muscles, creatine is converted to the high energy source creatine
phosphate (phosphocreatine)
Creatine
ATP
Creatine Kinase
ADP
Creatine phosphate
Creatine phosphate
• Creatine phosphate is a high-energy phosphate compound
• Acts as a storage form of energy in the muscle
• Provides a small but, ready source of energy during first few seconds of
intense muscular contraction
• The amount of creatine phosphate in the body is proportional to the
muscle mass
Creatine Phosphate
ADP
ATP
Creatine
ENERGY FOR
MUSCLES
DURING EXERCISE
(first few seconds)
Creatine degradation
1.
Creatine and creatine phosphate spontaneously form creatinine as an
end product
2.
Creatinine is excreted in the urine
3.
Serum creatinine is a sensitive indicator of kidney disease (Kidney
function test) i.e. serum creatinine increases with the impairment of
kidney function
Creatine Degradation
Creatine
ATP
ATP
ADP
ADP
Creatinine
CREATINE
DEGRADATION
IN MUSCLES
Creatine phosphate
Pi
BLOOD
Kidney
Urine
Creatinine in urine and plasma
•
Normal serum creatinine is 0.7 to 1.4 mg/dl (55-120µmol/L) and serum creatine level is 0.2
to 0.4 mg/dl
•
Serum creatinine is a sensitive indicator of kidney disease (Kidney function test) because
creatinine is normally rapidly removed from the blood and excreted
•
Urinary creatinine can be used to estimate muscle mass
As the amount of creatinine excreted in urine is proportional to the total amount of creatine
phosphate of the body & the amount of creatine phosphate in the body is proportional to
the muscle mass.
A typical male excretes about 15 mmol of creatinine per day
A decrease in muscle mass due to muscular dystrophy or paralysis leads to decreased amount
of creatinine in urine
•
The amount of creatinine in urine is used as an indicator for the proper collection of 24
hours urine sample (normal urinary output is 15-25 mg/kg/day)
Plasma creatinine & kidney functions
Creatinine is an end product of nitrogen metabolism and is excreted
in urine.
Plasma creatinine & creatinine clearance are used to assess
the kidney functions (Kidney function tests in labs).
Plasma creatinine Vs. Creatinine Clearance:
1- Plasma creatinine is more precise than creatinine clearance which
depends on urine volume for its calculation
2- Plasma creatinine is fairly constant through out adult life while
creatinine clearance declines with aging..
S
Plasma Creatine Kinase (CK)
• Creatine Kinase is responsible for the generation of creatine
phosphate in contractile muscular tissues (intracellular).
• Plasma CK levels are changed in disorders of cardiac and
skeletal muscle
Creatine
ATP
Creatine Kinase
ADP
Creatine phosphate
Plasma Creatine Kinase (CK) cont.
Creatine Kinase Isoenzymes:
Cretine Kinase (CK) enzyme is a protein formed of two subunits (B & M)
Accordingly, CK has 3 isoenzymes:
CK-3 (CK-MM), CK-2 (CK-MB) & CK-1 (CK-BB)
They have the same function BUT with some difference in structure
Skeletal muscle: > 98% CK-MM & 2 % CK-MB
Heart muscle: 70% CK- MM & 30%CK-MB
Brain : CK-BB
These isoenzymes can be separated using electrophoresis
Creatine Kinase & muscle diseases
• There are many enzymes as CK, AST & LDH may be increased in
muscle diseases.
• Plasma total CK is usually the measurement of choice
• Plasma CK is valuable in the diagnosis of myocardial infarction and
some skeletal muscle diseases
• Increase in plasma CK may occur after trauma or surgical
operation, intramuscular injections , after prolonged muscular
exercise.
Creatine Kinase & muscle diseases
In Duchenne muscular dystrophy
• Increase in total plasma CK at birth before onset of clinical
signs
• Plasma total CK is increased during early stages of the
disease & tend to fall at the terminal stage
• About 75% of female carriers of Duchenne dystrophy have
small increases in plasma CK
In neurogenic muscle disease: plasma CK is usually normal in
peripheral neuritis, polymyelitis
References
• Lippincott, Illustrated Biochemistry
• Bishop : Clinical Chemistry Principles,
Procedures Correlation 6th edition
• Lecture Notes in Clinical Biochemistry