1. Creatine Metabolism Energy to Skeletal Muscles Lecture-2

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

3. Production of ATP: Contraction requires huge amounts of ATP Muscle fibers produce ATP three ways: Phosphagens Aerobic metabolism Anaerobic metabolism

4. 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.

5. Three amino acids are required: Glycine Arginine Methionine (as S-adenosylmethionine) Site of biosynthesis: Step 1: Kidneys Step 2: Liver Creatine Biosynthesis

6. Arginine + Glycine Ornithine Amidino- transferase Guanidinoacetate SAM SAH Methyltransferase Creatine Kidneys Liver

7. 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

8. Creatine phosphate is a high-energy phosphate compound storage form of energy Acts as a storage form of energy in the muscle during first few minutes Provides a small but, ready source of energy during first few minutes of intense muscular contraction muscle mass The amount of creatine phosphate in the body is proportional to the muscle mass Creatine phosphate Creatine Phosphate Creatine ADP ATP ENERGY FOR MUSCLES DURING EXERCISE (first few minutes)

9. creatinine 1.Creatine and creatine phosphate spontaneously form creatinine as an end product urine 2.Creatinine is excreted in the urine 3.Serum creatinine 3.Serum creatinine is a sensitive indicator of kidney disease (Kidney function test). Serum creatinine increases with the impairment of kidney function Creatine degradation

10. Creatine Creatine phosphate ATP ADP ATP Creatine Degradation Creatinine Pi BLOOD Kidney Urine CREATINEDEGRADATION IN MUSCLES

11. Normal serum creatinine 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 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 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 15mmol 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 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

12. Creatinine is an end product of nitrogen metabolism and is excreted in urine. Plasma creatinine creatinine clearance Plasma creatinine & creatinine clearance are used to assess the kidney functions (Kidney function tests in labs). Plasma creatinine: 1- more precise than creatinine clearance which depends on urine volume for its calculation 2- is fairly constant through out adult life while creatinine clearance declines with aging.. Plasma creatinine & kidney functions

13. Creatine Kinase is responsible for the generation of creatine phosphate in contractile muscular tissues CK levels are changed in disorders of cardiac and skeletal muscle Plasma Creatine Kinase (CK) Creatine Creatine phosphate ATP ADP CreatineKinase

14. 1.CK is required for conversion of creatine into creatine phosphate 2.It is formed of two subunits (B & M) 3.CK has 3 isoenzymes: Skeletal muscle: > 98% CK-MM & 2 % CK-MB Heart muscle: 70% CK- MM& 20 & 30%CK-MB Brain : CK-BB These isoenzymes can be separated according to their physical properties using electrophoresis Plasma Creatine Kinase (CK)

16. There are many enzymes as CK, AST, LD & ALT may be increased in muscle diseases. Plasma total CK Plasma total CK is usually the measurement of choice (largest changes and the greatest number of cases of different etiologies) myocardial infarction some muscle diseases Plasma CK is valuable in the diagnosis of myocardial infarction and some muscle diseases Increase in plasma CK may occur after trauma or surgical operation, intramuscular injections, after prolonged muscular exercise. Creatine Kinase & muscle diseases

18. Lippincott, Illustrated Biochemistry Bishop : Clinical Chemistry Principles, Procedures Correlation 6 th edition Lecture Notes in Clinical Biochemistry References