BS2014: Bioenergetics & Muscle Metabolism

ATP synthesis pathways

• ATP-phosphocreatine system (anaerobic metabolism

• Glycolytic system

• Oxidative system

ATP-phosphocreatine system

• phosphorylation of ADP to replenish ATP

• conversion of PCr + ADP → Cr + ATP

• anaerobic = no oxygen required

• substrate level phosphorylation

• quick and efficient

• replenishes ATP stores during rest

• recycles ATP stores during exercise until used up

Enzyme catalysing ATP-phosphocreatine system

creatine kinase

Glycolytic system

• 2 phases: preparation & pay-off

• preparation: traps glucose in cell and forms a compound that is readily converted into 2 3C molecules, using 2 ATP

• pay-off: each 3C molecules produces 4 ATP + 2 NADH (2 ATP + 1 NADH each)

• net yield = 2 ATP + 2 NADH

Glycolysis

• Glucose conversion to fructose 1,6-bisphosphate, using 2 ATPs

• fructose 1,6-bisphosphate converted to 2 pyruvate (3C sugar), formation of pyruvate produces 2 ATP + 1 NADH

Substrate level phosphorylation

• direct transfer of a phosphate group from a donor molecule where the energy of hydrolysis is higher than that for ATP

• no oxygen required

Anaerobic glycolysis - lactate dehydrogenase

• used when oxygen supply is inadequate

• allows ATP formation of glycolysis by regenerating NAD via lactate dehydrogenase

NADH regeneration

lactate dehydrogenase converts pyruvate to lactate, forming NAD+ to keep glycolysis going

Cori cycle (lactate)

• Lactate from the muscle is converted to glucose in the liver (via conversion to pyruvate)

• glucose returns to the muscle and is used in glycolysis

2 main phases of Oxidative system

• Citric acid cycle

• Oxidative phosphorylation

Sources of energy in the body

• Carbohydrates

• Fats

• Proteins

Glycogen metabolism

• glycogenesis catalysed by glycogen synthase

• glycogenolysis catalysed by glycogen phosphorylase

Fat (triacylglycerol) metabolism

• hormonal signals control mobilisation/storage of TAGs in adipose tissue

• insulin promotes TAG storage

• glucagon/adrenaline promotes lipolysis

Energy systems used for ATP production in a short sprint

• PCr and anaerobic glycolysis

• PCr carbohydrate

Energy systems used for ATP production in a long distance run

• PCr system

• aerobic metabolism

• carbohydrate & lipid metabolism

Relative rate of ATP formed per second (for each energy system)

• ATP-PCr — 10

• anaerobic glycolysis — 5

• oxidative (carbohydrate) — 2.5

• oxidative (fat) — 1.5

ATP formed per molecule of substrate

• ATP-PCr — 1

• anaerobic glycolysis — 2-3

• oxidative (carbohydrate) — 31-38

• oxidative (fat) — >100

Available capacity of each system

• ATP-PCr — <15s

• anaerobic glycolysis — ~1 min

• oxidative (carbohydrate) — ~ 90 min

• oxidative (fat) — days

Oxidative capacity of muscle fibre types

• type I — high anaerobic endurance, can maintain exercise for prolonged periods, require oxygen for ATP production, efficiently produce ATP from fat & carbohydrates

• type II — poor aerobic endurance, fatigue quickly, produce ATP anaerobically

Regulation of insulin release at rest

• glucose entry through GLUT2 of pancreatic β-cells

• intracellular [ATP] rises

• inhibition of K_ATP depolarises the membrane

• influx of Ca²⁺ via VGCC

• increase in cytosolic [Ca²⁺] triggers insulin secretion

GLUT4

an insulin-regulated protein which transports glucose into skeletal muscles and adipose tissue

Insulin-induced GLUT4 expression

• insulin binds to its receptor

• activates PIP2 which activates PIP3 to release Akt

• Akt stimulates the movement of GLUT4 containing vesicles to the membrane

Insulin-induced glycogenesis

• activation of glycogen synthase to promote glycogen production

• inhibition of glycogen phosphorylase to slow glycogen breakdown

• high [ATP] inhibits glycolysis

Skeletal muscle during exercise

• energy demands rise

• fuel sources change in response to signals

• sources of ATP change

Observed changes in blood metabolites during prolonged, moderate exercise

• [blood glucose] is fairly constant

• [blood lactate] in fairly constant

• [blood glycerol] increases

• [blood insulin] decreases

• [blood FFA] increases

Why does [blood glycerol] and [blood FFA] increase with prolonged moderate exercise

TAGs from adipose tissue are being broken down into FFAs and glycerol to provide energy for muscle

Why does [blood glycogen] decrease during exercise

breakdown in the muscle to release glucose to provide energy

Why do we see an increase in lactate in the early stages of exercise?

• as the muscles are working to get enough oxygen, anaerobic glycolysis is occurring causing build up of lactate

• over time lactate levels decrease as it is being taken out of muscle

Major endocrine glands responsible for metabolic regulation

• anterior pituitary gland

• thyroid gland

• adrenal gland

• pancreas

Hormonal regulation of metabolism during exercise

• Adrenaline/noradrenaline — increases glycogenolysis and lipolysis

• Insulin/Glucagon — increases glycogenolysis and lipolysis

Regulation of glucagon release

• low [glucose] → VG Na⁺ and Ca²⁺ channels open to fire action potentials → influx of Ca²⁺ stimulate glucagon secretion

• high [glucose] → Na⁺ channel inactivation prevents Ca²⁺ influx and thereby inhibition of glucagon secretion

Sources of glucose during moderate exercise

• glycogenolysis in muscle (glycogen → glucose 6-phosphate) → used to power contraction

• glycogenolysis in liver (glycogen → glucose 6-phosphate) → secretes glucose into the blood which can be taken up by skeletal muscle to power contraction

• gluconeogenesis in the liver (lactate, glycerol, amino acids → glucose) → important source for powering muscle contraction

Drivers for insulin-independent glucpse uptake

• AMP

• Ca²⁺

Key regulatory enzymes for (insulin-independent glucose uptake in skeletal muscle)

• calmodulin kinase (CaMK) — phosphorylates SNARE proteins which leads to movement of GLUT4 to the cell membrane

• AMP-activated protein kinase (AMPK) — rends to be upregulated during exercise to allow movement of GLUT4 to the cell membrane

FFAs as major fuel in prolonged exercise

FFAs oxidised in muscle to generate acetyl-CoA and NADH for use in oxidative phosphorylation

Order of ATP-generation mechanisms in exercise

1. ATP-phosphocreatine

2. anaerobic glycolysis

3. oxidative phosphorylation using carbohydrates

4. oxidative phosphorylation using FFAs

Why doesn’t glycogenolysis occur in skeletal muscle

skeletal muscle does not contain glucagon receptors

Potential metabolic changes that occur as a result of aerobic training

• increase in skeletal muscle glycogen stores

• increase in skeletal muscle mitochondrial size

• increase in skeletal muscle mitochondrial number

• increase in skeletal muscle expression of glycolytic enzymes

• increase in skeletal muscle expression of citric acid cycle enzymes

• increase in skeletal muscle myoglobin content

Why do muscles with more type IIb fibres appear paler than those with a greater proportion of type I fibres

type IIb have a low myoglobin content

Effect of insulin

• promotes hepatic and skeletal muscle glycogenesis

• slows gluconeogenesis

• slows FFA mobilisation and promotes TAG storage

• activates fatty acid synthesis

Main effects of glucagon and adrenaline

• promotes hepatic and skeletal muscle glycogenolysis

• promotes gluconeogenesis

• promotes FFA mobilisation

• activates fatty acid oxidation