Intermediary Metabolism Crash Course pt 1

Intermediary Metabolism in the Myocardium

• Crash course on intermediary metabolism within the context of the myocardium (heart).
• Heart has a high fuel demand and uses three fuel types in order of preference:
  • Fatty acids (primary)
  • Glucose (secondary)
  • Ketone bodies (under fasting/starvation conditions)
• Focus on the roles of oxygen and ATP production in cardiac tissues.

Oxygen and ATP Production in Cardiac Tissues

• Drawing on hemoglobin and myoglobin knowledge for oxygen transport.
• The heart has a high oxygen consumption compared to other tissues.
• Primary energy sources:
  • Fatty acids (from triacylglycerols)
  • Glucose
  • Ketone bodies (reserve fuel)
• Comparison of glucose vs. fatty acid use for energy production.
• Methods of energy storage and limitations in cardiac muscle.

Storage

• Cardiac muscle preferentially stores fatty acids because it wants to burn them quickly for ATP regeneration.
• Storing fat around the heart can be problematic.
• The heart is among the most active tissues in the body.
• Myocardial function depends on equilibrium between work performed and energy synthesized (ATP).
• The heart needs to constantly regenerate ATP.
• The heart muscle is a highly oxidative tissue due to massive ATP regeneration using oxygen.
• The heart's metabolism is designed to regenerate large amounts of ATP via oxidative phosphorylation.
• Oxidative phosphorylation: Respiratory enzymes in mitochondria synthesize ATP from ADP, connecting inorganic phosphate back to ADP.

Fuel

• Requires a source of electrons from burning fuel (fatty acids, glucose) in the presence of oxygen.
• Under fed state basal aerobic conditions:
  • 60% of energy from fatty acids and triacylglycerols (broken down into free fatty acids)
  • 35% from carbohydrates (glucose)
  • 5% from amino acids and ketone bodies (mostly ketone bodies)
• Mitochondrial respiration produces >90% of energy for the myocardium.
• Myocardiocytes (heart muscle cells) have high mitochondrial content to mediate muscle contraction.
• 95% of ATP formation comes from oxidative phosphorylation in the mitochondria.
• More mitochondria = greater oxidative phosphorylation capacity = greater ATP regeneration.
• In the myocardium, 60-70% of ATP hydrolysis is for muscle contraction (releasing 35 \text{kJ/mol}).
• 30-40% of ATP is used to pump calcium back into the sarcoplasmic reticulum (endoplasmic reticulum in muscle cells).

Calcium Regulation

• Calcium must be pumped out of the cytosol to allow muscle relaxation.
• Free calcium in the cytosol acts as a second messenger ion.
• Calcium binds to molecules like calcium calmodulin, activating CAM kinase (second messenger amplification enzyme).
• CAM kinase transmits a chemical signal for the relaxation of the contracted muscle.
• Remember signal transduction cascades.

Myocardium Fuel Sources

• Resting state aerobic conditions:
  • 60% fatty acids (beta oxidation)
  • 35% glucose (glycolysis)
  • Ketone bodies (ketolysis)
• Acetyl CoA is an intersection substrate, derived from oxidation of fatty acids, glucose, and ketone bodies.
• Oxidation of fuels releases electrons and protons, captured in the TCA cycle, and used to reduce molecular oxygen to water, producing ATP.

Oxidation and Reduction

• Lose electrons oxidation (fuels).
• Gain electrons reduction (oxygen to water).
• Molecular oxygen gains electrons and protons to form water.
• Leo Gur: Lose electrons oxidation, gain electrons reduction.

Fed State Metabolism

• Pancreas releases insulin in response to high blood glucose.
• Insulin and glucose arrive at the liver, indicating which metabolic pathways to switch on/off.
• Insulin switches on glycolysis in the liver.
• Glucose is burned to pyruvate, pyruvate dehydrogenase forms acetyl CoA.
• Acetyl CoA enters the TCA cycle, producing NADH, FADH2, and ATP.
• Excess glucose forms glycogen (glycogenesis).
• Excess glucose, if ATP production and glycogen stores are maxed out, forms acetyl CoA.
• Acetyl CoA is converted to Citrate, then shuttled out of the mitochondria, and converted back to acetyl CoA to form new fatty acids (fatty acid synthesis).
• Fatty acids are used in the synthesis of triacylglycerols (TAGs) or lipogenesis.
• Lipids are either stay in the liver or bound to VLDL(very low density lipoprotein) for transport to adipocytes.

Heart

• VLDL delivers fatty acids to the heart for beta oxidation (major fuel supply).
• Blood glucose undergoes aerobic glycolysis for ATP regeneration.
• Small amount of glucose stored as glycogen.
• Ketone bodies make a negligible contribution under fed state.

Fasting State Metabolism

• Low blood glucose triggers glucagon release from the pancreas.
• Glucagon changes liver metabolism from insulin-based to glucagon-based.
• Glucagon shuts down glycolysis and activates gluconeogenesis.
• Gluconeogenesis: Creation of new glucose from non-glucose sources.
• Glycogenolysis: Breakdown of glycogen into glucose.
• Amino acids and lactate are used for gluconeogenesis.
• Lactate from red blood cells (lacking mitochondria) is converted back to glucose in the liver (Cori cycle).
• Fatty acids from adipocytes are converted to free fatty acids, and used for ATP production via beta oxidation.
• Oxaloacetate is diverted to gluconeogenesis, breaking the TCA cycle.
• Acetyl CoA from beta oxidation goes into ketogenesis (liver cannot burn ketone bodies).

Heart

• Beta oxidation remains the major source of ATP.
• Glucose is limited, supplemented by ketone bodies.
• The heart burns ketone bodies in preference to glucose, saving glucose for red blood cells.
• If the red blood cells die, all oxidative phosphorylation stops which leads to tissue death.

Starvation State Metabolism

• Glucose dominates the liver, emergency reserves are mobilized.
• The Cori cycle is heavily utilized.
• Muscle wastage occurs as amino acids are used for fuel (glucogenic and ketogenic amino acids).
• Glucogenic amino acids go into gluconeogenesis.
• Ketogenic amino acids go into acetyl CoA for ketogenesis.

Heart

• No glucose is burned.
• Only beta oxidation and ketolysis occur.

Red Blood Cells

• The red blood cells absolutely require glucose, and drive the metabolic switch because they always burn glucose. Then the brain will also use glucose.

Muscle Usage

• Breakdown of protein in muscles into amino acids.
• Glucogenic amino acids go into the TCA cycle and gluconeogenesis.
• Ketogenic amino acids go into acteyl CoA to support ketogenesis.

Protein

• Once all fat is wasted and muscle broken down, there are no more reserve fuel supplies for the heart, brain, and red blood cells.

Aerobic ATP Production

• The heart is a highly oxidative environment.
• Continuous oxygen supply is crucial to generate ATP.
• Reduction of oxygen into water also critical for heart's function.
• Rich blood supply from left and right coronary arteries is required.
• High density capillary bed (one capillary per cardiomyocyte) allows for extraction of 70% of oxygen.
• Resting blood flow is high, increasing five-fold during exercise.
• Occlusion of coronary arteries leads to myocardial infarction due to lack of ATP regeneration.

Contraction Occlusion

• Coronary arteries are occluded during each heartbeat cycle, momentarily depriving cardiomyocytes of oxygen.
• Weakened or stressed heart muscle can result from lack of proper ATP regeneration.
• Myoglobin:
  • Functions as a short-term oxygen store inside heart muscle cells.
  • Releases oxygen when blood flow is reduced during systole.

Myoglobin

• When partial pressure of oxygen falls below 10-15 mmHg, myoglobin releases oxygen.
• hemoglobin \text{ is sigmoidal curve}
• myoglobin \text{ is hyperbolic curve}
• Intracellular myoglobin can deliver 50% of its oxygen straight into the mitochondria.
• During relaxation, hemoglobin delivers oxygen to cardiomyocytes and recharges myoglobin.
• Myoglobin stores reserve oxygen for aerobic metabolism during brief heart occlusion.

Mitochondria

• Mitochondria constitute about 30% of myocardial cell volume and provide most of the ATP.

Summary

• Maintain uninterrupted blood supply.
• Constant fuel supply (fatty acids, glucose, ketone bodies).
• Maximum ATP produced under aerobic metabolism.
• Maximum re-supply of oxygen.
• Large amount of mitochondria in cardiomyocytes.
• 95% of fuel to regenerate ATP comes from fatty acids (65%) and glucose (35%), ketones 5%.

Oxidative Phosphorylation

• Electron transport chain and ATP synthase.
• Electron transport chain generates the proton gradient for ATP synthase to use.