Creatine Metabolism

Energy to Skeletal Muscles Lecture-2

• 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

Objectives

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.

Three amino acids are required:GlycineArginineMethionine (as S-adenosylmethionine)

Site of biosynthesis:Step 1: KidneysStep 2: Liver

Creatine Biosynthesis

Creatine Biosynthesis

Arginine + Glycine

Ornithine Amidino-transferase

Guanidinoacetate

SAM

SAH

Methyltransferase

Creatine

Kidneys

Liver

• 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)

Distribution of body creatine

Creatine

Creatine phosphate

ATP

ADP Creatine Kinase

• 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

Creatine Phosphate

Creatine

ADP

ATP ENERGY FOR

MUSCLESDURING EXERCISE

(first few seconds)

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

Creatine phosphate

ATP

ADP

ATP

ADP

Creatine Degradation

Creatinine

Pi BLOOD

Kidney

Urine

CREATINEDEGRADATION

IN MUSCLES

• 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)

Creatinine in urine and plasma

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 creatinine & kidney functions

• 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

Plasma Creatine Kinase (CK)

Creatine

Creatine phosphate

ATP

ADP

Creatine Kinase

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

Plasma Creatine Kinase (CK) cont.

• 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

Creatine Kinase & muscle diseases

• Lippincott, Illustrated Biochemistry• Bishop : Clinical Chemistry Principles,

Procedures Correlation 6th edition• Lecture Notes in Clinical Biochemistry

References