39d ago

Lactate Metabolism Notes

Lactate Metabolism

Learning Outcomes

  • Describe the evolution of lactate metabolism from a historical perspective to current evidence.

  • Explain the lactate shuttle(s) and the Cori cycle.

  • Understand:

    • Why lactate increases with intense exercise.

    • The biochemical basis of how lactate does not cause fatigue.

    • What the lactate threshold is and why we might want to measure it.

Lactic Acid vs. Lactate and H+

  • At physiological pH (7.4), lactic acid almost completely dissociates into lactate and hydrogen ions (H+).

Lactate and H+

  • Lactic acid in muscle was historically thought to be the cause of muscle fatigue.

  • During intense exercise, both lactate and H+ increase in muscle.

  • This is associated with a drop in muscle pH from ~7.05 to ~6.5. [What is pH?]

  • Fatigue can ensue with pH drop to as little as ~6.9.

Fletcher and Hopkins 1907

  • Frog muscles were stimulated to contract.

  • Lactate accumulated, and there was fatigue.

  • When fatigued muscles were put in an oxygen-rich environment, lactate disappeared.

Lactate: The Bad Guy?

  • During exercise under anaerobic conditions:

    • Fatigue occurs.

    • H+ increases.

    • Lactate is present.

  • Previously taught that with O2 you have pyruvate, and without O2 you have lactate.

  • Lactate:pyruvate ratio in resting muscle needs to be considered.

Hill and Lupton (1923)

  • There is a rise in lactate at the beginning of exercise.

  • This is because there is an O2 deficit (hypoxia) in exercising muscle.

1922 Nobel Prize – Hill and Meyerhof

  • Stimulated unperfused frog muscle to contract. Lactate produced, O2 required to remove.

  • Theory: Lactate produced because of a lack of O2 in contracting muscle (anaerobic metabolism).

  • Main theories:

    • O2 deficit

    • O2 debt

Oxygen Debt

  • It was believed that excess VO2 post-exercise was to “repay” the O2 deficit (i.e., get rid of La- produced as a result of the O2 deficit).

  • Believed that 20% La- was oxidised to provide ATP to convert the remaining 80% La- back to glycogen.

1930s - 1970s: Lactate’s Reputation as a Waste Product

  • Anaerobic metabolism produces ATP, which produces lactate – a waste product.

  • After exercise, to get rid of this “waste product”, the lactate is converted to glycogen (stored CHO).

  • This led to the concept of anaerobic/lactate threshold in the 1960s and 70s by Wasserman and colleagues.

Anaerobic/Lactate Threshold

  • Lactate threshold = The exercise intensity where blood lactate increases exponentially.

  • Reflects the last point (i.e., exercise intensity) where lactate entry into and removal from the blood are balanced.

  • A useful measure?

What is the Anaerobic Threshold?

  • Blood Lactate (BLa) and ventilation increases disproportionately to VO2.

  • Lack of O2 thought to increase anaerobic glycolysis and thus lactic acid.

  • Lactic acid doesn’t exist, so it dissociates to La- and H+ and were responsible for muscle acidosis.

  • The body attempts to buffer H+ resulting in increased CO2, a potent stimulus for respiration.

The Cori Cycle

  • Lactate is transported to the liver in the venous system.

  • Converted to glucose in the liver through a form of gluconeogenesis.

  • During exercise, roughly 25% of lactate is removed through the Cori cycle.

  • Screening for alcohol.

George Brooks – The Lactate Shuttle Pioneer

  • The historical view was that glycolysis (involving the production of lactate) and aerobic metabolism were separate.

  • Work by Brooks around 2000 proposed new mechanisms of lactate metabolism.

  • Lactate (the product of glycolysis) is actually a substrate for aerobic metabolism.

Intracellular Lactate Shuttle

  • Lactate can be moved around within the same cell and oxidised.

  • Components and processes include:

    • Sarcolemma

    • Glycogen

    • Glucose-6-Phosphate (G-6-P)

    • Lactate Transporter (LT)

    • Pyruvate

    • Glucose

    • Glycolysis (GL)

    • Tricarboxylic Acid cycle (TCA)

    • Carbon Dioxide (CO2)

    • Lactate Dehydrogenase (LDH)

Cell-Cell Lactate Shuttle

  • Lactate can be moved to other cells and tissues to be oxidised.

  • Involves:

    • Type I and Type IIa muscle fibres

    • Monocarboxylate transporters (MCT1, MCT4)

Lactate as a Signaling Molecule

  • Lactate acts as a potent signaling molecule in the body.

Causes of Lactate Accumulation with Increased Exercise Intensity

  • Lactate production increases as exercise intensity increases (rate of appearance (Ra)).

  • Lactate disappearance (Rd) does not increase to the same extent as the rate of appearance.

  • This leads to a net increase in blood (or muscle) lactate (Stanley et al., 1985).

Oxygen Deficit

  • Current evidence: O2 is available at the start of exercise.

  • But, there is an inability to utilise O2 in metabolic pathways and insufficient metabolic substrates at the start of exercise.

  • There is no oxygen deficit; La is produced as an integral part of aerobic metabolism.

Oxygen Debt (EPOC)

  • Phosphocreatine resynthesis in muscle

  • Lactate removal

  • Elevated hormone levels

  • Elevated heart rate and breathing rate post-exercise

  • Elevated core body temperature

  • Restoration of O2 stores in muscle and blood

Lactate and Muscle Fatigue

  • Correlation does not mean causation.

  • Force decreases as there is a decrease in intracellular pH.

  • But force recovers faster than the recovery in pH, suggesting a disconnect (Allen et al. 2008).

  • Lactate remains a useful measure to indicate the changes in metabolism with exercise.

Does Lactate Cause Fatigue? No!

  • Lactate is produced at rest.

  • The H+ produced as a result of lactic acid may not cause the reduction in pH (even if pH is a cause of fatigue).

  • Lactate may actually protect against acidosis (Robergs et al. 2004).

  • Lactate prevents pyruvate accumulation and supplies NAD(+) needed in phase 2 of glycolysis.

  • Lactate should not be seen as a glycolytic waste product nor as an acidifier.

  • Lactate; acidosis; and fatigue; are not equivalent in human physiology.

Lactate Production and Exercise Performance

  • Determinants of exercise performance:

    • HR max

    • SV max

    • Capillary density

    • Q max

    • [Hb]; % SaO2

    • [Ca – Cv O2] max

    • VO2 max

    • Oxidative enzymes

    • % VO2max at LT

    • Running economy

    • Velocity at LT

    • Max velocity in distance running

  • The LT is worth measuring, even if we do not fully understand the mechanisms.

Measuring the Lactate Threshold

  • Start at 9 km/h or 60 W.

  • 4 min per stage.

  • Increased intensity of 1 km/h or 20 W per stage.

  • 30 s rest per stage to allow for blood sampling (treadmill only).

Calculating the LT

  • Lactate threshold is calculated from plotting intensity (speed, power) on the x-axis and blood lactate concentration on the y-axis.

  • A curve is fitted, and LT determined using an equation of choice.

Maximum Lactate Steady State

  • MLSS = the highest blood La- and workload that can be obtained without continued blood lactate accumulation.

  • The blood La- concentration varies by < 1mmol/L during the last 20 mins of constant intensity exercise.

Training-Induced Adaptations to Blood Lactate

  • 16 weeks of physical training in 8 male students.

  • There is a rightward shift in the blood lactate concentration curve.

  • Can work harder before starting to accumulate blood lactate.

Summary

  • Lactate is not a waste product and does not cause fatigue!

  • Lactate can be shuttled between and within cells – oxidised to produce ATP or converted to glycogen in the liver.

  • Produced from anaerobic metabolism but can be a substrate for aerobic metabolism.

  • Lactate can be an important performance measure.


knowt logo

Lactate Metabolism Notes

Lactate Metabolism

Learning Outcomes

  • Describe the evolution of lactate metabolism from a historical perspective to current evidence.

  • Explain the lactate shuttle(s) and the Cori cycle.

  • Understand:

    • Why lactate increases with intense exercise.

    • The biochemical basis of how lactate does not cause fatigue.

    • What the lactate threshold is and why we might want to measure it.

Lactic Acid vs. Lactate and H+

  • At physiological pH (7.4), lactic acid almost completely dissociates into lactate and hydrogen ions (H+).

Lactate and H+

  • Lactic acid in muscle was historically thought to be the cause of muscle fatigue.

  • During intense exercise, both lactate and H+ increase in muscle.

  • This is associated with a drop in muscle pH from ~7.05 to ~6.5. [What is pH?]

  • Fatigue can ensue with pH drop to as little as ~6.9.

Fletcher and Hopkins 1907

  • Frog muscles were stimulated to contract.

  • Lactate accumulated, and there was fatigue.

  • When fatigued muscles were put in an oxygen-rich environment, lactate disappeared.

Lactate: The Bad Guy?

  • During exercise under anaerobic conditions:

    • Fatigue occurs.

    • H+ increases.

    • Lactate is present.

  • Previously taught that with O2 you have pyruvate, and without O2 you have lactate.

  • Lactate:pyruvate ratio in resting muscle needs to be considered.

Hill and Lupton (1923)

  • There is a rise in lactate at the beginning of exercise.

  • This is because there is an O2 deficit (hypoxia) in exercising muscle.

1922 Nobel Prize – Hill and Meyerhof

  • Stimulated unperfused frog muscle to contract. Lactate produced, O2 required to remove.

  • Theory: Lactate produced because of a lack of O2 in contracting muscle (anaerobic metabolism).

  • Main theories:

    • O2 deficit

    • O2 debt

Oxygen Debt

  • It was believed that excess VO2 post-exercise was to “repay” the O2 deficit (i.e., get rid of La- produced as a result of the O2 deficit).

  • Believed that 20% La- was oxidised to provide ATP to convert the remaining 80% La- back to glycogen.

1930s - 1970s: Lactate’s Reputation as a Waste Product

  • Anaerobic metabolism produces ATP, which produces lactate – a waste product.

  • After exercise, to get rid of this “waste product”, the lactate is converted to glycogen (stored CHO).

  • This led to the concept of anaerobic/lactate threshold in the 1960s and 70s by Wasserman and colleagues.

Anaerobic/Lactate Threshold

  • Lactate threshold = The exercise intensity where blood lactate increases exponentially.

  • Reflects the last point (i.e., exercise intensity) where lactate entry into and removal from the blood are balanced.

  • A useful measure?

What is the Anaerobic Threshold?

  • Blood Lactate (BLa) and ventilation increases disproportionately to VO2.

  • Lack of O2 thought to increase anaerobic glycolysis and thus lactic acid.

  • Lactic acid doesn’t exist, so it dissociates to La- and H+ and were responsible for muscle acidosis.

  • The body attempts to buffer H+ resulting in increased CO2, a potent stimulus for respiration.

The Cori Cycle

  • Lactate is transported to the liver in the venous system.

  • Converted to glucose in the liver through a form of gluconeogenesis.

  • During exercise, roughly 25% of lactate is removed through the Cori cycle.

  • Screening for alcohol.

George Brooks – The Lactate Shuttle Pioneer

  • The historical view was that glycolysis (involving the production of lactate) and aerobic metabolism were separate.

  • Work by Brooks around 2000 proposed new mechanisms of lactate metabolism.

  • Lactate (the product of glycolysis) is actually a substrate for aerobic metabolism.

Intracellular Lactate Shuttle

  • Lactate can be moved around within the same cell and oxidised.

  • Components and processes include:

    • Sarcolemma

    • Glycogen

    • Glucose-6-Phosphate (G-6-P)

    • Lactate Transporter (LT)

    • Pyruvate

    • Glucose

    • Glycolysis (GL)

    • Tricarboxylic Acid cycle (TCA)

    • Carbon Dioxide (CO2)

    • Lactate Dehydrogenase (LDH)

Cell-Cell Lactate Shuttle

  • Lactate can be moved to other cells and tissues to be oxidised.

  • Involves:

    • Type I and Type IIa muscle fibres

    • Monocarboxylate transporters (MCT1, MCT4)

Lactate as a Signaling Molecule

  • Lactate acts as a potent signaling molecule in the body.

Causes of Lactate Accumulation with Increased Exercise Intensity

  • Lactate production increases as exercise intensity increases (rate of appearance (Ra)).

  • Lactate disappearance (Rd) does not increase to the same extent as the rate of appearance.

  • This leads to a net increase in blood (or muscle) lactate (Stanley et al., 1985).

Oxygen Deficit

  • Current evidence: O2 is available at the start of exercise.

  • But, there is an inability to utilise O2 in metabolic pathways and insufficient metabolic substrates at the start of exercise.

  • There is no oxygen deficit; La is produced as an integral part of aerobic metabolism.

Oxygen Debt (EPOC)

  • Phosphocreatine resynthesis in muscle

  • Lactate removal

  • Elevated hormone levels

  • Elevated heart rate and breathing rate post-exercise

  • Elevated core body temperature

  • Restoration of O2 stores in muscle and blood

Lactate and Muscle Fatigue

  • Correlation does not mean causation.

  • Force decreases as there is a decrease in intracellular pH.

  • But force recovers faster than the recovery in pH, suggesting a disconnect (Allen et al. 2008).

  • Lactate remains a useful measure to indicate the changes in metabolism with exercise.

Does Lactate Cause Fatigue? No!

  • Lactate is produced at rest.

  • The H+ produced as a result of lactic acid may not cause the reduction in pH (even if pH is a cause of fatigue).

  • Lactate may actually protect against acidosis (Robergs et al. 2004).

  • Lactate prevents pyruvate accumulation and supplies NAD(+) needed in phase 2 of glycolysis.

  • Lactate should not be seen as a glycolytic waste product nor as an acidifier.

  • Lactate; acidosis; and fatigue; are not equivalent in human physiology.

Lactate Production and Exercise Performance

  • Determinants of exercise performance:

    • HR max

    • SV max

    • Capillary density

    • Q max

    • [Hb]; % SaO2

    • [Ca – Cv O2] max

    • VO2 max

    • Oxidative enzymes

    • % VO2max at LT

    • Running economy

    • Velocity at LT

    • Max velocity in distance running

  • The LT is worth measuring, even if we do not fully understand the mechanisms.

Measuring the Lactate Threshold

  • Start at 9 km/h or 60 W.

  • 4 min per stage.

  • Increased intensity of 1 km/h or 20 W per stage.

  • 30 s rest per stage to allow for blood sampling (treadmill only).

Calculating the LT

  • Lactate threshold is calculated from plotting intensity (speed, power) on the x-axis and blood lactate concentration on the y-axis.

  • A curve is fitted, and LT determined using an equation of choice.

Maximum Lactate Steady State

  • MLSS = the highest blood La- and workload that can be obtained without continued blood lactate accumulation.

  • The blood La- concentration varies by < 1mmol/L during the last 20 mins of constant intensity exercise.

Training-Induced Adaptations to Blood Lactate

  • 16 weeks of physical training in 8 male students.

  • There is a rightward shift in the blood lactate concentration curve.

  • Can work harder before starting to accumulate blood lactate.

Summary

  • Lactate is not a waste product and does not cause fatigue!

  • Lactate can be shuttled between and within cells – oxidised to produce ATP or converted to glycogen in the liver.

  • Produced from anaerobic metabolism but can be a substrate for aerobic metabolism.

  • Lactate can be an important performance measure.