Energy sources in muscle

Dr. Mummedy Swamy Dept of Chemical pathology PPSP, USM

Lecture topics

Energy sources in muscle

Energy sources for muscle Metabolic pathways providing acetyl-CoA Metabolic pathways utilizing acetyl-CoA Citric acid cycle Amino acid catabolism Electron trans port chain Oxidative phosphorylation

Metabolic pathways of energy production in muscle

Oxidative phosphorylation

Lecture contents

Introduction to muscle energy metabolism Sources of energy for muscle contraction Metabolic pathways producing acetyl-CoA

Carbohydrate metabolism

Glycogenolysis Anaerobic and aerobic glycolysis Pyruvate dehydrogenase reaction -oxidation Ketolysis

Lipid metabolism

Ketone bodies metabolism

Introduction

Muscle is the major transducer of chemical energy into mechanical energy The hydrolysis of ATP is used to drive movement of the filaments ATP in muscle is regenerated from ADP by:

Anaerobic or aerobic catabolic processes Substrate level phsporylation and oxidative phosphorylation Fast (white, anaerobic) twitch fibers Slow (red, aerobic) twitch fibers

Skeletal muscle contains

Skeletal muscle contain myoglobin as a reservoir of oxygen

Sources of energy for muscle contraction

Creatine phosphate ADP Glycogen (muscle stores) Glucose Fatty acids Amino acids Ketone bodies

Creatine phosphate

Creatine phosphate is readily available high-energy phosphate in muscle It prevents the rapid depletion of ATP ATP is generated from ADP by substrate level phosporylation The reaction is catalyzed by Creatine phosphokinase (CK)
Creatine phosphate + ADP
CK

Creatine + ATP

Same enzyme is used for creatine phosphate formation from ATP at times when the muscle is relaxed demands for ATP is not so great

Biosynthesis of creatine and creatinine

Amino acids used in the biosynthesis

glycine, arginine, and methionine Enzymes

1. Arginine-glycine transamidinase (kidney) 2. Guanidoacetate methyltransferase (liver) 3. Creatine phosphokinase (muscle)

Creatinine is formed nonenzymatically

1. The 24-hour excretion of creatinine in the urine is remarkably constant 2. It is proportionate to muscle mass

ADP

Adenylate kinase or myokinase reaction

2 ADP AMP + ATP

The above reaction is driven to right in the presence of AMP deaminase or 5nucleotidase
AMP AMP IMP + NH3 Adenosine + Pi

Adenosine increases blood supply to muscle IMP can be converted back to AMP in the presence of aspartate (purine nucleotide cycle)
IMP + Asp Adenylsuccinate AMP + Fumatate

Metabolic pathways

Anaerobic pathways

Aerobic pathways

Glycolysis Creatinine kinase reaction Adenylate kinase reaction

Glycolysis PDC reaction -Oxidation Ketolysis Oxidation of amino acid carbon skeleton Citric acid cycle Oxidative phosphorylation

Glycogen

Muscle contain large amounts of glycogen The release of glucose from glycogen is dependent on a specific muscle glycogen phosphorylase Ca2+, epinephrine, and AMP can activate the above enzyme

Cont

Glycogenolysis:

Breakdown of muscle glycogen Enzymes involved:

Glcogen phosphorylase Debranching enzyme Phosphoglucomutase Gucose-1-P Glucose-6-P

Glycogen + Pi Glucose-1-P

Muscle does not contain glucose-6phosphatase

Glucose

Anaerobic glycolysis
Glucose 2 Lactate + 2 ATP

Aerobic glycolysis
Glucose 2 Pyruvate + 2 ATP + 2 NADH

Pyruvate dehydrogenase reaction

Pyruvate Acetyl-CoA + NADH + CO2

Citric acid cycle

Acetyl-CoA 2 CO2 + CoA + 3 NADH + FADH2 + GTP

Oxidative phosphorylation (ETC)

NADH + Oxygen FADH2 + Oxygen 3 ATP + H2O 2 ATP + H2O

Glycolysis

It can occur in anaerobic & aerobic conditions Mainly in white (fast twitch) fibers, anaerobic glycolysis occurs
Glucose 2 Lactate + 2 ATP

The Cori cycle

Excessively produced muscle lactate is converted to glucose by gluconeogenisis in liver and released in to circulation to be used by muscle

Cont

Aerobic glycolysis: It occurs red (slow twitch) fibers,

Glucose 2 Pyruvate + 2 ATP + 2 NADH

In aerobic conditions pyruvate is converted to acetyl-CoA by PDH enzyme complex (PDC) Acetyl-CoA enters TCA cycle & completely oxidized to carbon dioxide Reduced coenzymes produced in glycolysis and TCA cycle enters ETC and produce ATP by oxidative phosphorylation

Reactions of glycolysis

Cont

Reactions of glycolysis:

Cont

In anaerobic conditions pyruvate is converted to lactate by lactate dehydrogenase (LDH)

Pyruvate + NADH
LDH

Lactate +NAD

In aerobic conditions pyruvate is converted to acetylCoA by pyruvate dehydrogenase complex (PDH / PDC)
Pyruvate + NAD + CoA
PDC

Acetyl-CoA +NADH + CO2

Acetyl-CoA enters the TCA cycle and degraded to carbon dioxide

Energetics of glycolysis

Energy used
glucose + ATP
Hexokinase

glucose-6-P fructose-1, 6- bis P

fructose-6-P + ATP

Phosphofructokinase

Energy produced
glyceraldehyde-3-P + NAD
Glyc-3-P dehydrogenase

1,3-bis phophoglycerate + NADH 3-phosphoglycerate + ATP pyruvate + ATP

1,3-bis phosphoglycerate + ADP Phosphoenol pyruvate + ADP

Phosphoglycerate kinase

Pyruvate kinase

Regulation & inhibition of glycolysis

Regulation:
1. 2.

3.

Hexokinase: Product inhibition Phospho fructokinase: Activation by AMP & fructose2, 6-bis phosphate. Inhibition by ATP & citrate Pyruvatekinase: Activation by fructose- 1, 6-bis phosphate. Inhibition by ATP, Acetyl-CoA, alanine, and PKA phosphorylation Iodoacetate: Glyceraldehyde-3-p dehydrogenase Fluoride: Enolase Ar or Hg ions complex the SH groups of lipoic acid and inhibit PDH and causes lactic acidosis

Inhibition:
1. 2. 3.

Pyruvate dehydrogenase reaction

Pyruvate + NAD + CoA Acetyl-CoA + NADH + CO2
The oxidation of pyruvate to acetylCoA is the irreversible route from glycolysis to citric acid cycle Pyruvate is oxidatively decarboxilated to acetyl-CoA Pyruvate dehydrogenase complex (a multienzyme complex) catalyses this reaction

Regulation of pyruvate dehydrogenase

Pyruvate dehydrogenase is regulated by end-product inhibition and covalent modification Pyruvate dehydrogenase is inhibited when the following ratios are high: ATP/ADP, acetyl-CoA/CoA, NADH/NAD All are high under conditions of fatty acid oxidation NADH/NAD ratio is high in extensive muscle activity

-Oxidation of fatty acids

Oxidation of fatty acids occurs in mitochondria Fatty acids are activated in cytoplasm before being catabolized Reaction is catalyzed by Acyl-CoA synthetase

Fatty acid transport into mitochondria

Long chain fatty acids penetrate the inner mitochondrial membrane as carnitine derivatives

Reactions of -Oxidation
The reactions proceed in a cyclic form Two carbons at a time are cleaved from acyl-CoA, starting from carboxyl end One cycle of -oxidation produces:
Acetyl-CoA, acyl-CoA (2 carbon shorter than original fatty acid), NADH, FADH2

Enzymes involved in -oxidation:

1. Acyl-CoA dehydrogenase 2. Enoyl-CoA hydratase 3. Hydroxyacyl- CoA dehydrogenase 4. Thiolase

Energetics of -oxidation

Energy using reaction:

Activation of fatty acid to fatty acyl-CoA

Fatty acid +ATP + CoA Acyl-CoA + Ppi + AMP

Energy producing reactions:

Oxidation of acyl-CoA by acyl-CoA dehydrogenase

acyl-CoA + FAD enoyl-CoA + FADH2

Oxidation of -Hydroxyacyl-CoA by dehydrogenase

-Hydroxyacyl-CoA + NAD -ketoacyl-CoA + NADH

Ketone bodies: Ketolysis