Module 3 - Carbohydrate Metabolism (Simplified)

Question 1

Where is CHO stored? (i.e. endogenous stores)

Answer 1

In the a) Liver; and b) Skeletal muscle as glycogen

Question 2

Individual glucose molecules are joined together via what enzyme?

Answer 2

Glycogenin

Question 3

What happens to glycogen content during exercise? (i.e. stored CHO as glycogen)

Answer 3

• Glycogen is broken down through glycogenolysis
• Releases individual glucose molecules from the core glycogenin protein, so it can be used by the muscle through glycolysis and aerobic processes to produce ATP

Question 4

CHO stores in skeletal muscle as glycogen

1) Concentration
2) How does this vary?
3) % of total CHO stores

Answer 4

1) 50-500 mmol/kg DM

2) Depends on training status, prior exercise and dietary CHO intake

3) 80% of total CHO stores

Question 5

CHO stores in liver as glycogen

1) Concentration
2) % of total CHO stores

Answer 5

1) Higher concentration than muscle

2) 10-15% of total CHO stores

Question 6

Other than CHO stores in muscle and liver, where is the remainder of CHO stored?

Answer 6

It circulates in the blood/plasma as glucose

• Glycogen stored in the liver can be broken down and released into circulation to maintain blood glucose levels

Question 7

What are the 2 primary factors that affect source of CHO use?

Answer 7

1) Intensity
2) Duration

Question 8

What source of CHO stores is preferred during high-intensity exercise (95-100% VO2max)?

Answer 8

Muscle glycogen

Question 9

What source of CHO stores is preferred during low-intensity exercise (25% VO2max)

Answer 9

• Very little glycogen breakdown occurs
• Contribution of both glycogen and glucose only account for 10-15% of total fuel source

Question 10

What happens to preferred use of CHO stores when exercise intensity increases?

Answer 10

Both glucose and glycogen become primary fuels oxidised to produce ATP to sustain exercise

Why?
- Because it recruits more fast-twist motor units

Question 11

What happens to CHO sources during prolonged exercise at moderate- to high-intensity exercise

Answer 11

• Contribute to 50% of total energy expenditure
• Rapidly depletes by 40-60% within first 90-120 mins
• Compensatory increase in reliance on blood glucose as primary CHO fuel source

Question 12

Bergstrom et al. 1967 - Classic study that manipulated the diet of individuals over three days prior to undertaking a single bout of cycling exercise at 70% VO2max to fatigue.

What happened when participants consumed inadequate CHO intake?

Answer 12

• Lower than average muscle glycogen content prior to exercise
• Cycled for ~60 mins before fatigue

Question 13

Bergstrom et al. 1967 - Classic study that manipulated the diet of individuals over three days prior to undertaking a single bout of cycling exercise at 70% VO2max to fatigue.

What happened when participants consumed normal CHO intake?

Answer 13

• Muscle glycogen content prior to exercise was 2-fold higher than low-CHO diet
• Cycled for ~120 mins before fatigue

Question 14

Bergstrom et al. 1967 - Classic study that manipulated the diet of individuals over three days prior to undertaking a single bout of cycling exercise at 70% VO2max to fatigue.

What happened when participants consumed high CHO intake?

Answer 14

• Muscle glycogen content was 3-4x higher than low-CHO diet
• Cycled for ~180 mins before fatigue

Question 15

Bergstrom et al. 1967 - Classic study that manipulated the diet of individuals over three days prior to undertaking a single bout of cycling exercise at 70% VO2max to fatigue.

Conclusion

Answer 15

That CHO loading prior to exercise and having high pre-exercise muscle glycogen content improves endurance exercise performance

Having low or inadequate glycogen levels can negatively impact performance

Question 16

Bergstrom et al. 1967 (i.e.Classic study) showed the effects of having adequate glycogen levels prior to exercise. However, participants that take part in endurance sports (longer than 2hrs) have high demands for CHO as a fuel, which is not met by endogenous muscle glycogen storage capacity or the athlete’s ability to replenish these stores between events/bouts of exercise. What does this mean?

Answer 16

The supply of exogenous CHO (i.e. through feeding of CHO or glucose during exercise) has also been explored as another strategy to improve endurance performance

Question 17

What is muscle glycogen breakdown?

Answer 17

The glycogen stored in skeletal muscle is broken down (via glycogenolysis), freeing those glucose molecules that muscle cells oxidise (through anaerobic or aerobic metabolism) to produce ATP needed for muscle contraction

Question 18

What is the primary factor that impacts the rate of muscle glycogen breakdown?

Answer 18

Exercise intensity

Low-int = rate is slow

Mod-int = faster rate than low-int, muscle glycogen content depletes @ 120 mins

High-int = much greater rap than lower intensities, muscle glycogen content depletes @ 60 mins

Question 19

What happens to muscle glycogen breakdown during exercise?

Answer 19

• Rate is most rapid during early stage of exercise, when amount of stored glycogen is at its highest
• Rate of breakdown declines as intensity and duration increases, due to a reduced availability of glycogen
• Compensatory increase in availability of blood glucose to be taken up by muscle to maintain CHO oxidation

Question 20

What is the primary rate limiting enzyme that regulates the breakdown of muscle glycogen (i.e. glycogenolysis)?

Answer 20

Glycogen phosphorylase

Question 21

How is glycogen phosphorylase (enzyme) controlled?

Answer 21

By altering the proportion of the enzyme in the less active ‘B’ form and the more active ‘A’ form

• Also known as allosteric regulation

Question 22

How is glycogen phosphorylase (enzyme) converted from its less active ‘b’ form, to its more active ‘a’ form?

Answer 22

• Caused by…

1) An increase in localised levels of calcium (due to muscle contraction)

2) Hormonal stimulation by adrenaline

Question 23

How is the activity of glycogen phosphorylase (enzyme) increased? (i.e.=more glycogen is broken down to produce ATP)

Answer 23

• By a rise in allosteric modulators - ADP, AMP, IMP and Pi
• These modulators occur in response to muscle contraction and when ATP supply is not meeting the demand

Question 24

How does glycogen concentration influence glycogen phosphorylase activity?

Answer 24

High levels of muscle glycogen concentration = increased rate of glycogen breakdown

(i.e. more glycogen available = more glycogen can be broken down)

Question 25

What is muscle glucose uptake?

Answer 25

When exercise begins (i.e. muscle contraction), the glucose circulating in the blood/plasma, is transported across the cell membrane, into the muscle, to then be broken down and made into ATP.

Question 26

What are the 3 primary steps to regulate the rate of glucose uptake, and ensure that this rate meets the energy demands of exercise?

Answer 26

1) Extracellular (outside the muscle) = influence glucose supply to the muscle (circulating glucose concentration, blood flow to contracting muscle)

2) Membrane = influence glucose transport across the plasma membrane or sarcolemma of the muscle, regulated by glucose transporters (GLUT4)

3) Intracellular (inside the muscle) = Influence processes within the muscle related to glucose utilisation or disposal (glycolysis, oxidative metabolism) or breakdown (glycogenolysis)

Question 27

What factors influence muscle glucose supply?

Answer 27

1) Blood flow
2) Blood glucose concentration

Question 28

What increases muscle glucose supply to working muscle during exercise?

Answer 28

1) Increased blood flow (more glucose is delivered to the working muscle to be taken up by the muscle)

2) Increasing blood glucose concentration (through ingesting glucose), meaning more glucose is available to the muscle

Question 29

How does circulating glucose get into skeletal muscle cells?

Answer 29

• Because the glucose concentration outside the muscle cell is higher than the inside, a concentration gradient exists for glucose to move into muscle cells (i.e. glucose moves from high to low concentration)
• Glucose transporters (GLUT + number to identify isoform; esp., GLUT4) translocate FROM a storage site inside the cell TO the cell surface (plasma membrane) where it facilitates diffusion of glucose

Question 30

What happens to blood glucose when you consume a meal or feeding glucose?

Answer 30

• Increased hormonal insulin from the pancreas, which is a feedback mechanisms that increases translocation of GLUT4 to the muscle cell or cell surface.

This…

1) increases muscle glucose uptake; and (i.e. more glucose is in muscle cell)

2) lowers blood glucose levels (i.e. less glucose is in circulation)

Question 31

How does muscle contraction stimulate GLUT4 to mediate muscle glucose uptake?

Answer 31

1) Intracellular calcium is released from sarcoplasmic reticulum, which activates calcium-activated enzymes (incl. calmodulin, calmodulin activated kinases) to activate GLUT4 translocation to the membrane

2) Other calcium sensitive signalling proteins can be activated to induce GLUT4 translocation (incl. protein kinase C, nitric oxide synthase)

3) Metabolic intermediates (incl. AMP activated protein kinase; AMPK) acts as a sensory of cellular energy charge, reflected by AMP/ATP and Creatine/Phosphocreatine ratios, which are altered in contracting muscle

Question 32

What happens once glucose is transported across the membrane into the cytosol?

Answer 32

1) Glycolysis; then
2) Oxidation

Question 33

What must occur before glucose can enter the metabolic pathway of glycolysis?

Answer 33

• It is phosphorylated by adding a phosphate group to glucose (G) by the enzyme ‘Hexokinase’, to form glucose-6-phosphate
• This traps the ‘free’ glucose inside the cell and ensures the concentration gradient of glucose across the membrane is maintained to allow glucose to enter the cell

Question 34

Why is G6P important for glucose uptake?

Answer 34

• It is a intermediate metabolite that can influence glucose uptake so it matches glucose supply or demand to the needs of the contracting muscle
• If it is not used in glycolysis, then it accumulates (increasing overall G6P) in the muscle cell, which can feedback to inhibit the hexokinase (i.e. there is already sufficient G6P, so there is no need for hexokinase to phosphorylate any more glucose)
• Which reduces glucose transport into the muscle cell

Question 35

What is the relationship between muscle glycogen availability and glucose uptake?

What about increases in exercise duration?

Answer 35

• Inverse
• Increase in muscle glycogen breakdown = increases G6P = inhibits glucose uptake into muscle
• With exercise duration, muscle glycogen levels are reduced = produce less G6P = allows more glucose to be taken up into muscle

Question 36

What is glycolysis?

Answer 36

• In order for skeletal muscle to generate ATP (via oxidation of CHO) a series of metabolic pathways take place - the first one being glycolysis
• Uses glycogen or glucose as its starting substrate, which are converted to the intermediate metabolite (G6P), which then passes through a series of reactions that form the glycolytic pathway

Question 37

What is oxidative phosphorylation (aka. aerobic metabolism)

Answer 37

• It is the 4th step on the respiratory chain
• Occurs in the mitochondria
• It is the process where electron transport from the energy precursors from the citric acid cycle (step 3) leads to the phosphorylation of ADP, producing ATP

Question 37

What are the 2 possible end products of glycolysis?

How do they differ?

Answer 37

1) Pyruvate is converted to Lactate
- Anaerobic
- During sprint activity - when demand for rapid ATP production + mitochondrial oxidation is limited

2) Pyruvate is converted to CO2 + H2O
- Aerobic
- During a long slow run, pyruvate can be transported into mitochondria, completely oxidised or broken down

Question 38

Step 1 of cellular respiration

Answer 38

Glycolysis

• Generates ATP
• Produces pyruvate for oxidation in the mitochondria
• Also produces 1x NADH, which is a key energy transfer intermediate (electron carrier) needed for step 4

Question 39

Step 2 of cellular respiration

Answer 39

Pyruvate processing

• Before pyruvate (produced from step 1) can be oxidised in the mitochondria, it needs to be converted to acetyl CoA
• Produces 1x NADH
• This reaction is regulated by the enzyme Pyruvate Dehydrogenase (PDH)

Question 40

Step 3 of cellular respiration

Answer 40

Citric acid cycle

• The converted acetyl CoA is broken down in the mitochondria, to generate ATP
• Produces carbon dioxide
• Also produces 1x NADH and 1x FADH2

Question 41

Step 4 of cellular respiration

Answer 41

Electron transport chain

• Uses the 3x NADH and 1x FADH2 produced in steps 1-3, along with oxygen, to produce ATP + water

Question 42

What is the role of pyruvate dehydrogenase

Answer 42

• Before pyruvate can be oxidised in the mitochondria, it must be converted to acetyl CoA
• The rate of aerobic ATP production in the mitochondria is influenced by this rate limiting reaction
• Pyruvate dehydrogenase helps to regulate this conversion of pyruvate to acetyl CoA

Question 43

How does pyruvate dehydrogenase controlled/regulated

Answer 43

• Through altering the proportion of the enzyme in the inactive vs. active form
• The conversion of these states is through covalent modulation or phosphorylation, meaning a phosphate group is added (by protein kinase) or removed (by protein phosphatase)

Question 44

What form is pyruvate dehydrogenase, in resting muscle?

What happens to it at the onset of exercise?

Answer 44

• In resting muscle (fat is the primary fuel source) = pyruvate dehydrogenase is inactive (PDHb)
• At the onset of exercise (muscle glycogen becomes major fuel source) = pyruvate dehydrogenase converts from inactive to active form (PDHa)

Question 45

How is the level of pyruvate dehydrogenase activation graded?

Answer 45

By the intensity of exercise

More intense exercise (90% VO2max) is going to have higher levels of activation, when compared to moderate- (65% VO2max) and low-intensity exercise (35% VO2max)

Question 46

How does increases in duration of exercise impact pyruvate dehydrogenase activation?

Why?

Answer 46

• Plateaus between 10-120 mins, then declines as duration continues (240 mins)
• Because there is a decrease in CHO availability and increased reliance of FAT

Question 47

In resting conditions, pyruvate dehydrogenase is in its inactive state (PDHb)

So is a phosphate group added or removed, and by what protein?

Answer 47

In it’s inactive state, a phosphate group has been added

Phosphorylated by pyruvate dehydrogenase kinase

Question 48

At the onset of exercise, pyruvate dehydrogenase is converted to its active state (PDHa)

So is a phosphate group added or removed, and by what protein?

What happens to the pyruvate?

Answer 48

In its active state, a phosphate group is removed

dephosphorylated by pyruvate dehydrogenase phosphatase

Pyruvate is then converted to Acetyl CoA

Question 49

What regulates pyruvate dehydrogenase to be converted from its inactive, to its active state?

Answer 49

• A localised change in muscle metabolites

1. Increased calcium (Ca2+) from muscle contraction
2. Increased ADP that reflects an increase in ATP demand
3. Increased pyruvate that results in an increase in glycolysis

• These 3 factors work to activate PDH, to convert pyruvate to acetyl CoA, which drive CHO oxidation in the mitochondria and increases aerobic ATP production

Question 50

During exercise, how is the level of pyruvate dehydrogenase activity fine-tuned?

Answer 50

• Through feedback processes that occur in localised changes in muscle metabolites that allosterically regulate the enzymes that control the phosphorylation status of PDH, which includes:

1. Increased Acetyl CoA and NADH. (end products of PDH reaction)
2. Increased ATP which reflects adequate ATP supply

• Lowers the activity of PDH by converting the enzyme into inactive PDHb