Regulation of Substrate Metabolism During Exercise

Energy Systems During Exercise

  • ATP-PCr System:
    • Provides energy for short, high-intensity activities.
  • Glycolytic System:
    • Breaks down glucose to produce ATP.
  • Oxidative System:
    • Uses oxygen to generate ATP from carbohydrates, fats, and proteins.

Substrates for Prolonged Exercise

  • Carbohydrates:
    • Muscle Glycogen: Stored glucose in muscles.
    • Plasma Glucose: Circulating glucose in the blood.
  • Fats:
    • Plasma FFAs: Free fatty acids in the blood.
    • Adipose Tissue Triglycerides: Stored fat in adipose tissue.

Metabolic Pathways in Muscle Contraction

The key metabolic pathways during exercise include:

  • Glucose Metabolism:
    • Glucose enters the muscle cell via GLUT1 and GLUT4 transporters.
    • Glycogen is broken down into glucose-6-phosphate (G-6-P) by glycogen phosphorylase.
    • Glycolysis converts glucose to pyruvate.
  • Fat Metabolism:
    • Albumin transports FFAs in the blood.
    • FFAs are taken up by muscle cells via FABP, FAT/CD36, and FATP.
    • Triglycerides are broken down into FFAs and glycerol via ATG lipase, HS lipase, and MG lipase.
  • Mitochondrial Oxidation:
    • Fatty acyl-CoA is transported into the mitochondria via CPT-I and CPT-II.
    • β-oxidation breaks down fatty acyl-CoA into acetyl-CoA, NADH, and FADH₂.
    • Acetyl-CoA enters the TCA cycle, producing ATP, NADH, and FADH₂.
    • The electron transport chain (ETC) uses NADH and FADH₂ to produce ATP.
  • ATP Regeneration:
    • ATP is regenerated from ADP and Pi via ATPase and creatine kinase (CK).

ATP Regeneration

The three primary systems for ATP regeneration are:

  1. ATP-PCr System
  2. Glycolytic System
  3. Oxidative System

Energy Requirements During Exercise

  • Short Duration, High Intensity:
    • Primarily relies on anaerobic systems (ATP-PCr and glycolysis).
  • Long Duration, Low Intensity:
    • Primarily relies on aerobic systems (oxidative metabolism).
  • The activation and contribution of energy pathways is not sequential & separate, it's overlapping.

Fuel Sources

  • Carbohydrates:
    • Blood Glucose: 4−4.5 mmol/l4-4.5 \, \text{mmol/l} (20g)
    • Muscle Glycogen: 80−100 g80-100\, \text{g}
    • Liver Glycogen: 300−800 g300-800\, \text{g}
  • Fats:
    • Adipose Tissue Triglycerides: ~ 10.5 kg10.5\, \text{kg}

Fuel Utilization

  • Carbohydrate Metabolism

    1. Glucose transport to and uptake by skeletal muscle
    2. Glycogenolysis
    3. PDH activation
    4. β-oxidation and production of acetyl CoA and reducing equivalents
    5. ATP produced through the respiratory chain (electron transport and oxidative phosphorylation)

  • Fat Metabolism

    1. Lipolysis of stored triacylglycerol (triglycerides).
    2. FFA transport to and uptake by skeletal muscle
    3. FFA transport into matrix of mitochondria
    4. β-oxidation and production of acetyl CoA and reducing equivalents
    5. ATP produced through the respiratory chain (electron transport and oxidative phosphorylation)

Regulation of Glucose Transport and Uptake

  1. Blood Glucose Concentration
    • Liver glucose production
    • Insulin/glucagon
    • Epinephrine/norepinephrine
    • Cortisol
  2. Blood Flow:
    • Autoregulation/neural control
  3. Muscle Contraction:
    • Activation of AMPK

Hormonal Regulation of Glycogenolysis

  • Adrenaline:
    • Activates glycogenolysis via the cAMP cascade (slow process).
  • Calcium Ions (Ca2+Ca^{2+}):
    • (From muscle contraction) directly activates phosphorylase kinase (fast process).

Pyruvate Dehydrogenase (PDH) Regulation

  • Activation:
    • PDH phosphatase activates PDH.
    • Activated by: Ca2+Ca^{2+}, Mg2+Mg^{2+}, ADP
  • Inhibition:
    • PDH kinase inactivates PDH.
    • Activated by: ATP, NADH, Acetyl-CoA
      Exercise releases Mg2+Mg^{2+} and Ca2+Ca^{2+} ions that activate PDH phosphatase.

Biochemical Process of Lipolysis

  • Degradation of triglycerides to glycerol and fatty acids.
  • Takes place in adipose tissue and skeletal muscle.
  • Regulated by hormones such as adrenaline and insulin.
  • Activated by the enzymes adipose triglyceride lipase (cleaves 1st FFA), hormone-sensitive lipase (cleaves 2nd FFA), and monoacylglycerol lipase (cleaves 3rd FFA).
  • Occurs during exercise (but not until 30-60 min into exercise) and >6 h after a meal

Regulation of Lipolysis

  • Activation:
    • High noradrenaline and adrenaline
    • Peptides
  • Inhibition:
    • Low noradrenaline and adrenaline
    • Insulin (due to stimulation by CHO)
    • Adenosine

FFA Transport into Skeletal Muscle

  • Fatty acid binding protein (FABP)
  • Fatty acid transport protein (FATP)
  • Fatty acid translocase (CD36)
  • Exercise training modulates FFA transport by increasing the abundance of FA transporters

Fatty Acid Transport into Mitochondria

  • FFAs are activated by ACS and CoA (uses 2 ATPs).
  • The activated FA attaches to a carnitine molecule by carnitine palmitoyl transferase (CPT-1).
  • CPT-1 transports the carnitine-FA molecule across the mitochondrial membrane but is inhibited by malonyl-CoA and ↓ in pH.
  • CPT-2 removes carnitine, leaving the activated FA in the matrix of mitochondria.
  • Carnitine translocates to the outer membrane to pick up another activated FA.

β-Oxidation

  • A 16-carbon FA will undergo 7 cycles of β-oxidation
  • Results in the formation of a series of acetyl-CoAs, which then enter the TCA cycle
  • 1 FADH and 1 NADH are formed per cycle
  • The number of cycles of β-oxidation that a FA goes through depends on the carbon number of the FA

ATP Yield from β-Oxidation

  • Total ATP yield per 16 carbon FA is 131 ATPs
    • 7 NAD = 21 ATPs (3 per NAD)
    • 7 FAD = 14 ATPs (2 per FAD)
    • 8 acetyl-CoA = 96 ATPs (12 per acetyl-CoA that passed through the TCA cycle)
    • 2 ATPs used in fatty acid activation by ACS and CoA

Factors Regulating Substrate Metabolism

  1. Exercise intensity
  2. Exercise duration
  3. Training status
  4. Sex
  5. Menstrual status
  6. Environment

Exercise Intensity

  • During low-intensity exercise, most of the fat oxidized is from plasma FA’s
  • During moderate-intensity exercise, 50% of the fat oxidized is derived from IMTGs
  • Carbohydrate oxidation rates increase during high-intensity exercise.
  • Fat oxidation rates decrease during high-intensity exercise, despite rates of lipolysis remaining high

George Brooks and the Cross-Over Concept

  • Introduced the cross-over concept. The cross over "point" is the intensity where the contributions of carbohydrate and fat oxidation are equal.

AMPK

  • AMP-activated protein kinase (AMPK) is activated when ATP levels fall & AMP levels rise due to cellular stress, such as exercise
  • AMPK is inactivated when ATP levels in the cell are high
  • AMPK restores cellular energy balance by inhibiting ATP-consuming pathways & activating ATP-producing pathways

Fat Oxidation Rates and Exercise Intensity

  • Absolute rates of fat oxidation increase from low to moderate-intensity exercise, although relative contribution was decreased
  • Maximal rates of fat oxidation observed at 63% VO2VO_2max in untrained individuals
  • At higher exercise intensities, fat oxidation is inhibited both in absolute and relative terms

Reasons for Decreased Fat Oxidation at High Intensities

  1. ↓ FA release/availability
  2. ↓ FA uptake into the muscle cell
  3. ↓ FA uptake into mitochondria

Lipolysis and Exercise Intensity

  • Adrenaline (epinephrine) activates the conversion of inactive HSL to active HSL
  • Insulin deactivates conversion of inactive HSL to active HSL
  • AMPK is a fuel sensor that also upregulates HSL
  • A dose-dependent relationship exists between exercise intensity and adrenaline release

Blood Flow to Adipose Tissue

  • Ability to access large TAG stores might be compromised during high-intensity exercise because blood flow is redistributed to skeletal muscle and away from adipose tissue

Heparin and Fat Oxidation

  • Infusion of intralipids (triacylglycerols) with heparin restores FA concentrations to levels observed during moderate-intensity exercise
  • Fat oxidation slightly increased but still lower than moderate exercise intensities
  • Therefore, another intrinsic mechanism must be primarily driving the decrease in fat oxidation during high-intensity exercise

Fatty Acid Uptake

  • High-intensity exercise upregulates the activation of FAT/CD36 and FA uptake
  • Intramuscular long-chain fatty acid concentrations increase during high-intensity exercise.

LCFA Entry into Mitochondria

  • Oleate is a LCFA that requires a transporter
  • Octanoate is a MCFA that does not require a transporter
  • Percentage of oleate oxidised was reduced at high-intensity exercise.
  • No change in octanoate with high-intensity exercise

Malonyl-CoA

  • A potent inhibitor of CPT1 under resting and low-intensity exercise conditions
  • Experimental data supporting this theory is limited since muscle malonyl-CoA content remains unchanged during exercise at 90% VO<em>2VO<em>2max, compared with 60% VO</em>2VO</em>2max

Muscle Carnitine Content

  • If acetyl-CoA formation from oxidation of pyruvate as part of CHO metabolism during high-intensity exercise exceeds rate of utilization by TCA cycle, carnitine acts as a buffer for excess acetyl-CoA by combining with acetyl-CoA to form acetylcarnitine through the action of carnitine acetyl transferase (CAT)
  • However, this use of carnitine reduces the amount of free carnitine available to act as a substrate for CPT1, thereby inhibiting FA uptake into the mitochondria and reducing fat oxidation rates at high exercise intensities

Muscle pH

  • Drop in muscle pH with high-intensity exercise reduces CPT1 activity
  • In vitro data simulated high-intensity exercise by dropping pH from 7.0 to 6.8
  • Resulted in 30-40% decrease in CPT1 activity
  • More work required in humans

Exercise Duration

  • Exercise duration also regulates carbohydrate and fat oxidation rates

Training Status

  • Endurance training increases whole-body fat oxidation rates during exercise
  • One of the most profound adaptations to endurance training is a decreased reliance on the oxidation of carbohydrate and increased reliance on fat during exercise

Sex Differences

  • Mediated by higher oestrogen levels and/or lower testosterone levels in women
  • Does stage of the menstrual cycle impact substrate utilization during exercise?

Exercise in the Heat

  • Exercise in the heat increases reliance on carbohydrate oxidation, as mediated by elevations in adrenaline

Exercise in the Cold

  • Exercise in the cold decreases reliance on fat oxidation, as mediated by a reduction in blood flow to subcutaneous adipose tissue elevations in adrenaline

Key Takeaways

  1. The activation and contribution of energy pathways to ATP resynthesis is overlapping
  2. Carbohydrate stores are limited but can regenerate ATP fast enough for high-intensity exercise
  3. Fat stores are abundant but cannot regenerate ATP fast enough for high-intensity exercise
  4. Exercise modulates oxidative carbohydrate metabolism by upregulating intramuscular GLUT4 translocation and PDH activity
  5. Exercise intensity is the primary factor that regulates substrate metabolism during exercise
  6. Fat oxidation rates decrease at high exercise intensities due to a decrease in FFA availability and a reduced uptake of FFA into the muscle mitochondria
  7. Other factors that influence substrate metabolism include training status, sex, menstrual phase(?), and environment