KNES 373 Quiz 2

• Extracts potential energy from food & conserve it in ATP bonds

• Transfers the chemical energy of ATP to biological work

Chemical work

Mechanical work

Transport work

Adenosine Triphosphate

• 3 phosphate groups

• 1 Adenosine

• The bond breaks between phosphates 2 & 3

• 7.3 Kcal free energy is liberated (reduced) + Pi

ATP hydrolysis

• Decomposition reaction with water

  • ATP + H2O → ADP + Pi + (-7.3 kcal)

• Enzyme: ATPase

• 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)

• 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

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

By having a small amount of ATP, any changes in its concentration will be quickly detected & the corresponding metabolic responses will be activated

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

• 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

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

Hydrolysis reactions

Condensation reactions

Enzymatic (Oxidation & reduction) 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

• 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

• Oxidation - losing electrons

• Reduction - gaining electrons

• aka REDOX reactions

• Oxidation & reduction always happens together

• Often involve coenzymes

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

Ca2+

• ↑ in Ca2+ means we need to resynthesize ATP via troponin/tropomyosin

Metabolites

• ADP, AMP, Pi, H+

Mitochondrial reduction/oxidation state

• NAD+/NADH

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

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

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

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+

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

Enzymes contributing to the control of the rate of a reaction

• The activity of RLE depends on accumulation of substrate further down the pathway

FALSE

Signals related to muscle contraction “turn on” pathways to generate ATP (e.g. Creatine kinase reaction)

ATP demand during exercise ↑ up to 100-fold?

Minimal changes to ATP during exercise

aka Anaerobic metabolism

• doesn’t need oxygen (happens in the presence of O2 but doesn’t need it)

Occurs outside mitochondria

1. Glycogenolysis

2. Glycolysis

3. Lactate Production

Carbohydrates

Only macronutrient that can generate ATP both anaerobically & aerobically

Available:

• blood

• muscle

• liver (to muscle via blood)

• ingested (from digestion to muscle via blood)

Glucose transporter (GLUT4)

• transport protein (not an enzyme)

• specific to muscle cells

• facilitated diffusion

  • follows concentration gradient

• insulin-sensitive

Indirect cascade that should occur

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 → G6P → Pyruvate

What type of reaction is this?

REDOX reaction

2 Net ATP

• 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

• Rate-limiting enzyme

  • Increased activity: Ca2+, AMP, Pi, epinephrine

  • decreased activity: H+, ATP, G6P

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 → G6P (Hexokinase - HK)

G6P → Pyruvate (phosphofructokinase - PFK)

• When exercising

G6P → Glycogen (glycogen phosphorylase - PHOS)

• Not exercising

Either goes out of the cell or gets converted back to pyruvate via LDH

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

Throughout the 30s:

PCr contribution: ↓

Glycolysis Contribution: ↓

Oxidative phosphorylation contribution: ↑

Anaerobic metabolism is critical for transitions to higher workloads as well as maximal workloads

Glycogenolysis:

• glycogen phosphorylase (PHOS)

• phosphoglycomutase converts G1p to G6P

Glycolysis:

• Glucose transporter 4 (GLUT4)

• hexokinase (HK)

• phosphofructokinase (PFK)

Lactate production:

• lactate dehydrogenase (LDH)

Depends on exercise intensity

Aerobic - pyruvate

anaerobic - lactate

• 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

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

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

Aka tricarboxylic acid (TCA) or Krebs cycle

Activated by: Ca2+, ADP, NAD+

Oxaloacetate is reformed each cycle

Changes in ATP (a decrease in ATP)

TRUE

Low intensity:

• Pyruvate can enter the cell (mitochondria)

High intensity:

• pyruvate begins to accumulate outside the cell & therefore gets converted to lactate

It activates group III/IV afferents

Pi & H+ ions

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)

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

Complexes 1, 3 & 4

• 3 has no proton transfer

• 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

2 ATP

2 NADH + H+ (5 ATP)

2 Pyruvate

6 NADH (15 ATP)

4 CO2

2 FADH2 (3 ATP)

2 ATP

2 NADH (5 ATP)

2 CO2

6 CO2

4 ATP

10 NADH (25 ATP)

2 FADH2 (3 ATP)

Oxidative phosphorylation

• Lipolysis & free fatty acid uptake in skeletal muscle

• beta-oxidation

• oxidative phosphorylation

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

Involves the breakdown of triglycerides

• Releases the attached FFA tails from the glycerol backbone

Via Hydrolysis

Enzyme: Adipose triglyceride lipase (ATGL)

Triglyceride → Diglyceride → Monoglyceride → glycerol

Each break down results in the release of a FFA

FFA carried by albumin in blood

• enter via carrier proteins or facilitated diffusion

• chaperoned by fatty acid binding protein (FABP) in cell

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

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

To convert fatty acyl-CoA to acetyl CoA so it can enter the TCA cycle

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

18C free fatty acid = -2ATP

NADH & FADH2 = 32 ATP

9 Acetyl-CoA → TCA cycle = 90 ATP

1 Free Fatty Acid = 120 ATP

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

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

Pulmonary gas exchange

• O2 uptake & CO2 production

Arterial & venous blood sampling

Muscle biopsies

Stable isotopes

Respiratory exchange ratio

carbon dioxide production divided by oxygen uptake

RER = VCO2 / VO2

If RER = 1.0

• Fuel: carbohydrates

If RER = 0.71

• Fuel: lipid

If RER is b/w 0.71 & 1.0

• Fuel: mix

produce more kcals than fat

• more efficient

• Exercise intensity

• exercise duration

• substrate availability

• sex

• training status

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

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

muscle glycolysis & glycogenolysis

plasma FFA & triglycerides

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

• 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

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

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)

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)

Fat produces almost twice the amount of energy per gram of substrate

but

carbs are more efficient per unit of oxygen (require less O2)

FALSE

enhances endurance performance

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

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

Catabolic

• epinephrine / norepinephrine

• cortisol

• growth hormone

• glucagon

Anabolic

• Insulin

increases

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

During exercise, we see a depletion in glycogen

Redundant (multiple systems)

• increase in plasma epinephrine

• increase Ca2+ during muscle contraction

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

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

Insulin

• anabolic hormone

↑ muscle protein synthesis & ↓ muscle protein breakdown

↑ FFA & triglyceride synthesis in adipose tissue & liver

↑ glycogen synthesis & ↓ glycogenolysis in liver & muscle