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MET1 > Extremes of Metabolism > Flashcards

Extremes of Metabolism Flashcards

1
Q

What are the different types of muscle fibres and what are their metabolic preferences?

A
  • Muscle fibres are generally classified as:
  • Type 1 or slow twitch fibres – rely on glucose and FA for energy
  • Type 2 or fast twitch fibre – rely mostly on glycogen for energy. Further divided in:
    o Type 2A – have myoglobin so able to undergo oxidative phosphorylation
    o Type 2B – rely on anaerobic glycolysis
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2
Q

Which type of muscle fibre has the highest fatigue rate? And the lowest?

A 
Highest = Type 2B
Lowest = Type 1
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3
Q

How can metabolic demands change during exercise?

A
  • During extreme exercise the demand for ATP in skeletal muscle can increase 100 –fold.
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4
Q

How much energy is released by each source?

A

Creatine phosphate = 15kJ
Muscle glycogen = 8000kJ
Fatty acids = 17500kJ

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5
Q

How is energy supplied during short term exercise?

A
  • For short term exercise (100m sprint), the glycogen stores in the muscle should supply enough energy (ATP)
  • The break down of glycogen to ATP occurs in response to muscle contraction which releases calcium in response to nerve signalling.
  • Calcium activates CAMKinase
  • CAMK activates glycogen phosphorylase which catalyses the breakdown of glycogen to glucose -1-phosphate
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6
Q

How might TCA cycle be controlled in response to exercise?

A
  • Major control of the TCA cycle is the PDC which is regulated by phosphorylation by PDK/PDP
  • High levels of ADP, NAD+ and low levels of ATP, NADH inhibit the PDK while Calcium activates PDP maintaining the PCD in its active state!
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7
Q

What is another way that the TCA cycle may be controlled?

A
  • Calcium and ADP also drive the activity of two dehydrogenase enzymes in the TCA cycle to maintain high ATP production.
  • There is also a pull from high NAD+ levels
  • Oxygen dependent!
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8
Q

What is a major driver to energy production in muscle during exercise?

A

Calcium

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9
Q

What is another regulator of energy in exercise? How does this work and what does it stimulate?

A

AMP

  • During exercise, ATP levels run low and AMP levels start going up.
  • Like calcium, AMP has a number of effects on multiple pathways that drive energy production.
  • AMP stimulates:
    1. Increased glucose uptake (recruitment of GLUT4 to the membrane of muscle cells)
    2. Allosterically activates inactive glycogen phosphorylase (glycogenolysis) – de-phosphorylated GP is usually inactive - AMP can allosterically render it active.
    3. Allosterically activates PFK-1 (glycolysis)
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10
Q

What is AMP kinase (AMPK) and how is it activated?

A
  • High levels of AMP also activates an important kinase enzyme – AMPK
    o Plays a number of roles in also encouraging quick and constant production of ATP
    o Made up of 3 sub-units (α,β, γ). The γ sub-unit acts as an energy sensor.
    o AMPK has 3 major influences on energy production.
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11
Q

What are the 3 major influences of AMPK in energy production?

A
  1. Promotes the recruitment of GLUT4 glucose transporters to the membrane of muscle cells (an insulin-independent effect!)
  2. AMPK activates PFK2 enzyme, which catalyses:
    F6P -> F2,6-bP;
    an allosteric activator or PFK1. This occurs only in cardiac muscle.
  3. AMPK phosphorylates acetyl coA carboxylase. rendering it inactive. This stops the production of malonyl coA which usually inhibits the carnitine shuttle. Released of this inhibition, the carnitine shuttle will move more FA into the mitochondria allowing their lipolysis to release ATP.
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12
Q

What are the effects of AMPK in exercise (related to FA metabolism)?

A
  • During prolonged exercise (marathon running) the energy requirements shift from glucose to fatty acid break down as a source of ATP.
  • AMPK is a major regulator if this shift.
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13
Q

What is the nickname for AMPK and why?

A
  • AMPK is called the master regulator of cellular energy metabolism due to its many effects on glucose, lipid and protein metabolism.
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14
Q

What are the 6 main effects of AMPK?

A 
Glucose uptake
Fatty acid oxidation
Glycolysis
Gluconeogenesis
Glycogen synthesis
Glycogen synthesis
Fatty acid and cholesterol synthesis
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15
Q

What happens when you run out of energy (hit the wall)?

A
  • What happens you run out of energy – you “hit the wall”
  • Energy depletion:
    o 1st: run out of phosphocreatine
    o 2nd: run out of glycogen (700g of glycogen need for a marathon; body only has 500g in storage – 400g in muscle + 100g in liver)
    o 3rd: Over-reliance on FA metabolism for energy: lipolysis has an energy output of 60% at maximum rate, so might not meet the energy needs
    o FA oxidation is slower, requires more oxygen than glycolysis and TCA cycle ATP generation.
    o 4th: lactic acid build up decreases the pH in muscles and slows glycolysis and oxidative phosphorylation
    -
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16
Q

What are causes of insufficient mitochondria? How can this be improved?

A
  • Insufficient mitochondria – mitochondria lessen with age and inactivity (obesity). Increased by training.
17
Q

What is the priority during starvation? What changes may happen in the metabolism?

A
  • Priority: production of glucose (brain) – reduction in basal metabolic rate
  • Steps of changes in metabolism:
    1. Glucose levels start falling; insulin goes down, glucagon up
    2. Glycogen breakdown begins and can sustain body for about 30 hours
    3. Switch to FA break down which can sustain body for 2-3 days
    4. After 2 days gluconeogenesis and production of ketone bodies becomes only source of glucose & energy.
    5. Last resort for glucose is breakdown of protein (muscle) to release amino acids for gluconeogenesis
18
Q

How is alcohol metabolised?

A
  • Metabolized in the liver; in 3 ways:
  • Most common pathway involves the enzyme alcohol dehydrogenase (ADH) (90%)
  • Acetate can be converted to acetyl-coA
  • Acetaldehyde is toxic and carcinogenic; causes hangover so needs to be removed.
19
Q

Which ethnic group has a genetic predisposition to hangovers and why? How is this treated?

A 
-	People of Asian decent have a genetic predisposition to hangovers:
o	deficiency of acetaldehyde dehydrogenase (ALDH2) enzyme due to the rs671 polymorphism is 30-50% of pop
o	Disulrifam (anatabuse) – drug used to treat alcoholics- inhibits ALDH2 activity
20
Q

What are the metabolic impacts on alcoholics?

A
  • Alcoholics generally have a poor diet and derive most of their energy from alcohol
  • Alcohol metabolism produces increased NADH and increased acetyl coA:
    1. Inhibit GAPDH and pyruvate dehydrogenase enzymes (TCA cycle)
    2. Activates lactate dehydrogenase (drives lactic acid)
    3. Inhibit malate dehydrogenase (gluconeogenesis) increases
21
Q

What are the energy requirements of immune cells? How are these met and in which cells? What are these substances used for? What is the result of a failure in this process?

A
  • Have highly variable energy requirement
  • Immune cells have an increased requirement for the co-factor NADPH
  • (different from NADH)
  • in order to produce it, glucose is shuttled from glycolysis to the PPP
  • This occurs in macrophages, neutrophils and activated dendritic cells.
  • NADPH is used for:
    1. As a reducing agent (much like NADH)
    2. To generate ROS (reactive oxygen species)
  • Immune cells use NADPH oxidase to reduce O2 to oxygen free radical and then H2O2 (peroxide).
  • Peroxide is then used to kill engulfed pathogens in what is called a respiratory burst.
  • Failure to produce ROS in immune cells causes Chronic Granulomatous Disease.
22
Q

Why do immune cells need their energy metabolism to be highly versatile?

A
  • General energy metabolism in immune cells is highly versatile since many intermediate are needed as substrates in other biosynthetic pathways:
    o G6P in PPP
    o succinyl coA -> heme (enzyme catalase) -> ROS
    o Glutamine/glutamate are important intermediates that can feed in the TCA cycle to maintain a constant supply of oxaloacetate
    o Immune cells (and brain) are only cells to be energy selfish
     Take priority over other tissues when it comes to energy supply.
23
Q

Why do cancer cells required high metabolic activity?

A

To maintain a constant dividing population

24
Q

What is the most notable change in cancer metabolism and how does this affect the cell?

A
  • Most notable change in cancer metabolism is the WARBURG EFFECT/HYPOTHESIS:
    o Cancer cells tend to take up much more glucose than normal cells ( basis of PET scan)
    o Glucose tends to be used for aerobic glycolysis rather than oxidative phosphorylation, which means cancer cells prefer generating ATP through glycolysis rather than through oxidative phosphorylation (TCA cycle) even in the presence of oxygen.
    o Leads to build up of lactic acid in cancer cells
25
Q

What are possible advantages/explanations of the Warburg effect in cancer cells?

A
  • Possible advantages/explanations of the Warburg effect:
    1. Cancer cells require many metabolites which they get by taking intermediates from the TCA cycle. Might be TCA cycle is not completed due to shuttling off of intermediates
    2. Can also be a problem of oxygen supply. Inner cells in a tumour are far from capilleries and lack oxygen  activation of HIF1 could cause Warburg effect.
    3. Make up for lack of TCA cycle by increasing glucose uptake and rate of glycolysis (200X)
26
Q

How can metabolism be used in cancer treatment?

A

Can be used as a drug target

27
Q

Summarise extremes of metabolism.

A
  • Different types of muscle fibres rely on different sources and pathways of energy production.
  • Calcium (through CAMK) and AMP are important allosteric activators that drive enzymes that regulate glycolysis and TCA cycle to maintain energy production in aerobic conditions.
  • AMP activates AMPK that also promotes energy production by (1) increasing GLUT4 receptors, (2) activating PFK2, (3) inhibiting ACC enzymes.
  • Sequence of energy sources used during starvation; coordinated organ action
  • Alcohol metabolism – liver breaks down alcohol to acetaldehyde  acetate  acetyl coA  ketone bodies
  • Metabolic effect of alcohol abuse on other pathways and clinical symptoms
  • Immune cells: produce ROS (NADPH) to kill bacteria; important biosynthesis shift; energy selfish
  • Cancer cells: Warburg effect – preference for aerobic glycolysis

MET1 (16 decks)

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