What is the biological function of our body? (2)
Extracts potential energy from food & conserve it in ATP bonds
Transfers the chemical energy of ATP to biological work
ATP will be used for:
Chemical work
Mechanical work
Transport work
Describe the structure of ATP
Adenosine Triphosphate
3 phosphate groups
1 Adenosine
Between which phosphate group does the bond break & how much energy is released?
The bond breaks between phosphates 2 & 3
7.3 Kcal free energy is liberated (reduced) + Pi
Through what process is ATP broken down?
Describe this process
What enzyme is used
ATP hydrolysis
Decomposition reaction with water
ATP + H2O → ADP + Pi + (-7.3 kcal)
Enzyme: ATPase
Describe the general process through which potential energy is transferred from food to ATP
Energy is transferred using chemical compounds
Food energy is released in small quantities through stepwise metabolic reactions
Energy released by a reaction is transferred to chemical structures of another molecule (not in a form of heat)
The food has a very high Ep, as it gets broken down ATP is produced & Ep decreases (think of burger)
Describe this diagram:
ATP is added to fuel due to the thermic effect of feeding (energy required to break down food)
Each process requires energy & energy is lost to heat in all reactions
Each rectangle decreases in size with each stage because potential energy gets weaker as the stages progress
How much ATP is stored in our body & why
80-100g of ATP mostly stored in muscle cells
Why?
ATP is recycled (we resynthesize it)
via anabolism & catabolism
ATP is a very big molecule & having a lot is not very efficient
Why do we have a limited amount of ATP
By having a small amount of ATP, any changes in its concentration will be quickly detected & the corresponding metabolic responses will be activated
What are enzymes
Related to the rate that cells transfer energy
Proteins that accelerate a chemical reaction by reducing its activation energy
less energy needed to initiate reaction
Describe the important properties of enzymes:
Do not cause the reaction
Do not change energy yield of reaction
output stays the same
Are not consumed or changed during reaction
reusable
Sensitive to changes in temperature & pH
sometimes they react to changes in pH and/or temp
Describe the Lock & Key Hypothesis
Substrate fits into the active site of the enzyme like a lock fitting a key (highly specific)
The enzyme itself doesn’t change at all but it facilitates the breakdown of a substrate
Name three types of enzymatic reactions
Hydrolysis reactions
Condensation reactions
Enzymatic (Oxidation & reduction) reactions
Describe hydrolysis reactions
Decomposition reaction with water
catabolize/degrade complex molecules
a molecule of water is added to a substance; thus, both substance & water molecule to split into 2 parts
1 big molecule breaks-down into 2 sub-molecules with water
Describe condensation reactions
Opposite of hydrolysis
two molecules combine to build a single larger molecule with the loss of water
water is produced from the reaction
the process where water vapour in the air is changed into liquid water
Describe enzymatic reactions
Oxidation - losing electrons
Reduction - gaining electrons
aka REDOX reactions
Oxidation & reduction always happens together
Often involve coenzymes
Where do muscle cells use ATP? (distribution)
75% mechanical work
Myosin ATPase (breaking myosin-actin cross-bridges)
20% SERCA
Sarco/endoplasmic reticulum ATPase
calcium withdrawal/reuptake following contraction (taking Ca2+ from endoplasmic reticulum back to SR)
5% Ionic Transfer
Na+/K+ ATPase
moving sodium & potassium in & out of the cell
What signals are used to match ATP demand with ATP synthesis?
Ca2+
↑ in Ca2+ means we need to resynthesize ATP via troponin/tropomyosin
Metabolites
ADP, AMP, Pi, H+
Mitochondrial reduction/oxidation state
NAD+/NADH
What are the 3 metabolic pathways to resynthesize ATP
Immediate / phosphagen / alactic system (ATP-PCr system)
Adenosine triphosphate & phosphocreatine
Glycolytic / lactic / anaerobic system
glycogenolysis & glycolysis
lactate production
fastest pathway
Oxidative / aerobic system
different sources (carbs, lipids, protein, lactate)
oxidative phosphorylation
How does the immediate system resynthesize ATP?
What are the two reactions of the immediate system?
Resynthesizes it via stored ATP
Phosphocreatine (PCr)
PCr + ADP + H+ → ATP + Cr
used to resynthesize ATP
Adenylate Kinase
ADP + ADP → ATP + AMP
ATP → ADP + Pi + H+
enzyme: ATPase
Describe Creatine Kinase
Activated by:
PCr + ADP + H+ → ATP + Cr
Occurring all the time
First line of defense - ATP buffer
b/c we have way more PCr than ATP
Activated by:
↑ ADP
↓ ATP
Describe Adenylate Kinase
Myokinase (ADK) / Adenylate Kinase (ADK)
Quantitatively insignificant source of ATP during exercise
occurs during high-intensity exercise
removes adenine nucleotides from pool (increases recovery time)
ADP + ADP → ATP + AMP
AMP + H+ → IMP + NH4+
Describe the immediate / ATP-PCr system
When does it occur?
What happens as soon as muscle contraction starts?
What happens at exhaustion?
Can act in the presence of oxygen but doesn’t need it
Occurs during the first few seconds of exercise (3-15s)
ATP is maintained but PCr decreases
As soon as muscle contraction starts:
ATP is hydrolized to ADP + Pi + H+
↑ Ca2+ and by-products (ADP, Pi, H+)
Ca2+ & by-products activate CK enzyme
CK accelerates breakdown of PCr
PCr gives one Pi to ADP to resynthesize AT
PCr + ADP + H+ → ATP + Cr
The ATP that’s generated frmo the oxidative metabolism will be used to synthesize PCr
At exhaustion:
Both ATP & PCr decreases which prevents further muscle contractions
What is Rate Limiting Enzyme (RLE)
Enzymes contributing to the control of the rate of a reaction
The activity of RLE depends on accumulation of substrate further down the pathway
T/F: The reduction of ATP itself is a signal for ATP resynthesis
FALSE
Signals related to muscle contraction “turn on” pathways to generate ATP (e.g. Creatine kinase reaction)
ATP demand during exercise ↑ up to _______?
Minimal changes to _____ during exercise
ATP demand during exercise ↑ up to 100-fold?
Minimal changes to ATP during exercise
What 3 processes occur in the glycolytic system?
Where does glycolytic system take place
aka Anaerobic metabolism
doesn’t need oxygen (happens in the presence of O2 but doesn’t need it)
Occurs outside mitochondria
Glycogenolysis
Glycolysis
Lactate Production
What is the fuel that can produce energy aerobically & anaerobically?
Carbohydrates
What is a Carbohydrate?
Where is it available during exercise?
Only macronutrient that can generate ATP both anaerobically & aerobically
Available:
blood
muscle
liver (to muscle via blood)
ingested (from digestion to muscle via blood)
How does glucose enter a muscle cell?
______ sensitive
Glucose transporter (GLUT4)
transport protein (not an enzyme)
specific to muscle cells
facilitated diffusion
follows concentration gradient
insulin-sensitive
Indirect cascade that should occur
What happens to glucose when it enters a muscle cell?
Hexokinase (HK)
Converts glucose to glucose-6-phosphate (G6P)
ATP is hydrolized to ADP + Pi + H+
Pi will be attached to glucose to produce G6P
G6P cannot leave the cell (irreversible reaction)
G6P has two fates:
undergoes glycolysis
stored as glycogen
phosphoglucomutase converts G6P to G1P
glycogen synthase converts G1P to glycogen
Phosphofructokinase (PFK)
Rate-limiting enzyme
activated by: ADP, AMP, Pi, G6G (subtrate)
inhibited by: ATP, H+
Yields 2 ATP (Substrate level phosphorylation)
Requires 2 ATP
Produces 4 ATO
Yields 2 NADH + H+
oxidized by laactate dehydrogenase
glucose → ? → ?
What type of reaction is this?
glucose → G6P → Pyruvate
What type of reaction is this?
REDOX reaction
What is the net ATP production from 1 glucose molecule?
2 Net ATP
Describe Glycogenolysis
Where does Glycogenolysis occur?
ATP produced?
Occurs in sarcoplasm (outside mitochondria)
Glycogen breaks down to Glucose-1-phosphate
The reaction is catalyzed by glycogen phosphorylase (PHOS)
Activated by PA
Yields 3 ATP
Requires 1 ATP
Produces 4 ATP
What is glycogen phosphorylase (PHOS)
What increases & decreases activity?
Rate-limiting enzyme
Increased activity: Ca2+, AMP, Pi, epinephrine
decreased activity: H+, ATP, G6P
Fill out the table:
What is Lactate Dehydeogenase
Converts Pyruvate to lactate & lactate to pyruvate
When pyruvate & NADH + H+ accumulate, lactate is formed
mismatch b/w glycolytic rate & capacity of mitochondria to accept pyruvate
Glucose gets converted to G6P w/ what enzyme?
G6P either gets converted to pyruvate or glycogen, what state do these occur & what enzymes facilitate them?
Glucose → G6P (Hexokinase - HK)
G6P → Pyruvate (phosphofructokinase - PFK)
When exercising
G6P → Glycogen (glycogen phosphorylase - PHOS)
Not exercising
How does lactate get removed
Either goes out of the cell or gets converted back to pyruvate via LDH
How does lactate production relate to exercise intensity?
Lactate cannot cause fatigue, H+ causes fatigue
Signal: ATP demand > aerobic metabolism ATP supply
Lactate increases to a certain point then remains constant because lactate starts to get converted to pyruvate
Describe energy metabolism during intense exercise (30s all-out cycling)
Throughout the 30s:
PCr contribution: ↓
Glycolysis Contribution: ↓
Oxidative phosphorylation contribution: ↑
Anaerobic metabolism is critical for transitions to ? as well as ?
Anaerobic metabolism is critical for transitions to higher workloads as well as maximal workloads
Describe the enzymes of glygenolysis, glycolysis & lactate production
Glycogenolysis:
glycogen phosphorylase (PHOS)
phosphoglycomutase converts G1p to G6P
Glycolysis:
Glucose transporter 4 (GLUT4)
hexokinase (HK)
phosphofructokinase (PFK)
Lactate production:
lactate dehydrogenase (LDH)
What is the end-product of glycolysis?
Depends on exercise intensity
Aerobic - pyruvate
anaerobic - lactate
What happens to pyruvate in the mitochondria?
Goes to mitochondria matrix
Pyruvate → Acetyl-CoA + CO2
Facilitated by PDH
NAD+ → NADH+H+
In the conversion, each pyruvate molecule loses one carbon atom w/ the release of carbon dioxide
during the breakdown of pyruvate, electrons are transferred to NAD+ to produce NADH, which will be used by the cell to produce ATP
What is PDH
Purpose?
Activated/deactivated by
Pyruvate dehydrogenase
Reduces the level of lactate
controls rate of carbohydrate entry into mitochondria
Activated by Ca2+
deactivated by acetyl-CoA, ATP, NADH
Irrebersible: Traps acetyl-coA in mitochondria
What is a Coenzyme?
Examples:
A non-protein substance that is required for an enzyme to catalyze a reaction
they cannot by themselves catalyze a reaction
Examples:
NAD+ or NADH
FAD or FADH2
NAD+ & FAD are electron transporters
What is the citric acid cycle?
Activated by?
What’s reformed each cycle?
Aka tricarboxylic acid (TCA) or Krebs cycle
Activated by: Ca2+, ADP, NAD+
Oxaloacetate is reformed each cycle
What activates creatine kinase?
Changes in ATP (a decrease in ATP)
T/F Sensitivity of changes to ATP, ADP, etc change depending on the individual
TRUE
How does exercise intensity determine when pyruvate enters the cell?
Low intensity:
Pyruvate can enter the cell (mitochondria)
High intensity:
pyruvate begins to accumulate outside the cell & therefore gets converted to lactate
Why does lactate cause central fatigue?
It activates group III/IV afferents
What causes peripheral fatigue?
Pi & H+ ions
Draw the citric acid cycle
What is oxaloacetate?
Oxaloacetate:
Oil for the engine
TCA cycle works w/ oxaloacetate (its always there)
Acetyl-Coa
Raw material
ATP
Currency of our muscles
NADH & FADH2
Alternate forms of currency
they go to bank (ETC) to get exchanged into dollars (usable currency)
Draw the electron transport chain & describe it
Involves 4 protein complexes in the inner mitochondrial membrane:
Dehydrogenase enzymes remove electrons from hydrogen
Electrons are passed along cytochomes
pump hydrogens to the intermembrane space
creates a proton gradient
protons pass through ATP synthase
for every 4H+ transferred through ATP synthase, 1 ADP + Pi produces 1 ATP
oxygen is the final electron acceptor
reduced to water
What complexes in the ETC have a proton transfer?
Complexes 1, 3 & 4
3 has no proton transfer
What occurs w/ ATP synthase?
NADH & FADH2?
Catalyzes the formation of ATP from ADP & Pi
Driven by influx of H+ into mitochondria matrix
1 NADH is worth 2.5 ATP
b/c it translocates 10 H+ ions
1 FADH2 is worth 1.5 ATO
b/c it translocates 6 H+ ions
Glycolysis produces how much from 1 glucose?
ATP
NADH + H+ (ATP)
Pyruvate
2 ATP
2 NADH + H+ (5 ATP)
2 Pyruvate
What’s produced from the Citric Acid cycle
NADH (ATP)
CO2
FADH2 (ATP)
ATP
6 NADH (15 ATP)
4 CO2
2 FADH2 (3 ATP)
2 ATP
What is produced from pyruvate dehydrogenase?
NADH (ATP)
CO2
2 NADH (5 ATP)
2 CO2
What is the total yield produced from aerobic glycolysis?
CO2
ATP
NADH (ATP)
FADH2 (ATP)
6 CO2
4 ATP
10 NADH (25 ATP)
2 FADH2 (3 ATP)
What is slow to activate but has the greatest capacity to produce ATP?
Oxidative phosphorylation
What 3 things are included within the lipid aerobic system?
Lipolysis & free fatty acid uptake in skeletal muscle
beta-oxidation
oxidative phosphorylation
Describe the structure of a triglyceride
Where are they stored?
How does it relate to ATP
Only lipid that is a major source of energy (ATP) for muscle
Structure:
glycerol backbone
3 free fatty acid tails
Stored in adipose tissue or skeletal muscle
What is the purpose of lipolysis
Involves the breakdown of triglycerides
Releases the attached FFA tails from the glycerol backbone
Via Hydrolysis
Enzyme: Adipose triglyceride lipase (ATGL)
How is a triglyceride broken down via lipolysis?
Triglyceride → Diglyceride → Monoglyceride → glycerol
Each break down results in the release of a FFA
Describe lipid uptake
FFA carried by albumin in blood
enter via carrier proteins or facilitated diffusion
chaperoned by fatty acid binding protein (FABP) in cell
How do FFAs get into the mitochondria?
FFA is converted to fatty acyl-CoA & transported unto the mitochondria
occurs via fatty acyl-CoA synthase
FFA is like the line of grocery carts, this is difficult to transfer in the mitochondria & therefore need to be activated to fatty acyl-CoA
What is the Carnitine Shuttle?
Plays an essential role in the transfer of long-chain fatty acids across the inner mitochondrial membrane
Shuttle going in & out taking fatty acyl-CoA inside the mitochondria
What is the purpose of beta oxidation?
To convert fatty acyl-CoA to acetyl CoA so it can enter the TCA cycle
Describe beta-oxidation
Input
Output
Input:
Fatty acyl-CoA
FAD
NAD+
CoA (enzyme)
Output:
Acetyl-CoA + fatty acyl-CoA (n-2)
NADH
FADH2
Fatty acyl-CoA shrinks by 2-carbons every cycle
18C FFA goes through 8 cycles
At the end of the final cycle, 2 carbon-acetyl-CoA molecules are left
18-2 (n-2) = 16 ÷ 2 = 8 cycles
What is the ATP production from beta-oxidation
18C free fatty acid = -2ATP
NADH & FADH2 = 32 ATP
9 Acetyl-CoA → TCA cycle = 90 ATP
1 Free Fatty Acid = 120 ATP
What is the total yield from aerobic metabolism of triglycerides?
ATP from glycerol backbone
ATP from 3 FFA
Glycerol backbone
Enters glycolysis
16 ATP
Beta oxidation
3 x 18C FFA
360 ATP
Total yield:
376 ATP from 1 triglyceride
How does carbohydrate oxidation (glucose) compare to Free fatty acid oxidation (stearic acid) for ATP production?
FFA oxidation is going to produce more ATP per gram
BUT
more oxygen is needed to get the same amount of ATP from lipid compared to carbohydrates
THEREFORE
per unit of oxygen, carbohydrates are more efficient
What methods are used to assess fuel use?
Pulmonary gas exchange
O2 uptake & CO2 production
Arterial & venous blood sampling
Muscle biopsies
Stable isotopes
What is RER?
Respiratory exchange ratio
carbon dioxide production divided by oxygen uptake
RER = VCO2 / VO2
How do you know if carbohydrates or lipids are being used as fuel using RER?
If RER = 1.0
Fuel: carbohydrates
If RER = 0.71
Fuel: lipid
If RER is b/w 0.71 & 1.0
Fuel: mix
Per litre of O2, carbohydrates produce ? kcals than fat
produce more kcals than fat
more efficient
What influences substrate oxidation (whether we use lipid or carbohydrate)?
Exercise intensity
exercise duration
substrate availability
sex
training status
Describe substrate oxidation and exercise intensity in terms of percentage
Fat oxidation - major energy source
at rest to ~60-65% of VO2max
Carbohydrate oxidation - major energy source
60-65% of VO2 max
Lipid is used sparingly when exercise intensity is greater than 65% of VO2 max
Describe substrate oxidation and exercise intensity in terms of total energy
25% VO2max
65% VO2max
85% VO2max
25% VO2max
Majority contribution = plasma FFA
65% VO2max
Muscle glycogen comes into action
85% VO2max
Reduction in fat metabolisms
Increase in glucose & glycogen
Trend:
As intensity increases, Fat metabolisms decrease & carbohydrate metabolisms increase
There are exponential increments in ? as functions of relative exercise intensity
muscle glycolysis & glycogenolysis
There is multicomponent response of ? utilization w/ different intensity exercise
plasma FFA & triglycerides
carbohydrate loading before exercises increases ?
carbohydrate loading before exercises increases carbohydrate oxidation & glycogenolysis
If you consume carbohydrates prior to exercise, body is going to use those carbs for energy first (higher RER)
No carbohydrate consumption
plasma glucose decreases
burn fat
What is the effect of elevating pre-exercise muscle glycogen contents above normal resting values?
High-intensity
Moderate (low) intensity
Fatigue
Performance improvements?
No effect on high-intensity exercise lasting less than 5 min
no effect on moderate (low) intensity lasting 60-90 min
postpones fatigue by 20% in endurance events lasting more than 90 min
2-3% performance increase
How does sex influence substrate oxidation
Higher fat oxidation during exercise in females
contributes to a higher percentage of energy production compared to males
Males use more carbohydrate oxidation
get fatigued faster
Impact of training status on substrate oxidation
Trained individuals have a lower RER at higher exercise intensities b/c they use fat oxidation & not carbohydrates so they can maintain glycogen (prevent fatigue)
Compared to untrained individuals w/ a lesser aeroic capacity, endurance-trained athletes w/ a greater aerobic capacity:
Perform a given task at ?
derive a lower percentage of energy from ?
drives a greater percentage of energy from?
Perform a given task at a lower relative exercise intensity
derive a lower percentage of energy from carbohydrate fuel sources (glycogen, glucose, lactate)
drives a greater percentage of energy from lipid energy sources (plasma FFA, intramuscular triglycerdies)
What is the advantage of lipid oxidation?
Fat produces almost twice the amount of energy per gram of substrate
but
carbs are more efficient per unit of oxygen (require less O2)
T/F: Preloading muscle glycogen above normal resting values has no effect on endurance performance
FALSE
enhances endurance performance
Describe an overview of the body’s response to exercise
Exercise results in stress responses
Endocrine system produces hormones transferred via blood
Target tissue - cellular receptors interaction w/ hormones
Results in homeostatic & allostatic responses to manage stress responses
How does glucose & fat regulate exercise?
Exercise
Decrease intra & extracellular substrate (glycogen, FFA, etc)
Need to replace these substrates
Endocrine systen
Produces glucagon, EP, NEP, cortisol
hormones get released
Target tissue
Liver & muscle cells
Glucose & fat regulation
hormones increase glucose, glycogen & FFA levels
Fill out the table
What are the catabolic & anabolic hormones (5)
Catabolic
epinephrine / norepinephrine
cortisol
growth hormone
glucagon
Anabolic
Insulin
During exercise, the rate of carbohydrate & oxidation ?
increases
Describe the hormonal control of substrate mobilization during exercise
3 pathways activated by catecholamines (EP & NEP)
Liver:
glycogen → glucose
Adipocyte:
Triglycerides → FFA + glycerol
Tissue:
↑ FFA oxidation
Tissue:
Glucose entry to the muscle is blocked (during exercise)
These maintain blood glucose
Once we have these three pathways, we don’t need glucose to the muscle anymore which is why we block it
Muscle glycogenolysis is triggered by ?
During exercise, we see a depletion in glycogen
Redundant (multiple systems)
increase in plasma epinephrine
increase Ca2+ during muscle contraction
Insulin & Glucagon
Role:
They are called:
2 hormones respond to the same stimulus
They result in opposite responses regarding the mobilization of lower glucose & adipose tissue FFA
aka Counter-regulating hormones
Describe the 2 mechanisms for skeletal muscle glucose uptake:
Insulin signalling
Secrete insulin which leads to a cascade that mobilizes GLUT4 & activates vesicles
Muscle Contractions
Mechanical stretch via Ca2+ & AMP that does the same thing
What hormones acts to decrease blood glucose & how does it do it
Insulin
anabolic hormone
↑ muscle protein synthesis & ↓ muscle protein breakdown
↑ FFA & triglyceride synthesis in adipose tissue & liver
↑ glycogen synthesis & ↓ glycogenolysis in liver & muscle