Module 9: Muscle Role in Metabolic Complications Flashcards

1
Q

3 pathways that have been implicated in the
development of insulin resistance in skeletal
muscle

A
  1. Ectopic lipid accumulation leading to lipotoxicity.
  2. Pro-inflammatory cytokines from adipose tissue that travel to the muscle.
  3. Recruitment of pro-inflammatory macrophages directly into muscle.
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2
Q

What is ectopic lipid accumulation

A

significant accumulation of fat in tissues where it should not be stored

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3
Q

Increased NEFA release from adipose tissues causes:

A

Increased fat deposition in other tissues (muscle, liver)

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4
Q

IMCL (intramyocellular lipid) is positively corrrelated with

A

BMI, waist-to-
hip ratio, and % body fat

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5
Q

IMCL is inversely coorelated with

A

Insulin sensitivity

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6
Q

Athlete’s Paradox

A

High IMCL, high insulin sensitivity. high oxidative capacity, high muscle TAGS

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7
Q

Obesity is associated with an increase of: (3 answers)

A

-TAG
-DAG
-Ceramides

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8
Q

Over-expression of DGAT1: (increases w exercise)

A

increase muscle TAG (convert DAG to TAG), reduce both DAG and ceramides
-increases amount of GLUT4 at membrane
-prevent phosphoryl JNK and serine-phosphoryl IRS increase

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9
Q

Reducing DAG improves:

A

-glucose tolerance
-insulin sensitivity

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10
Q

Increasing GLUT4 at membrane affect:

A

-improve glucose uptake
-improve insulin sensitivity
-reduce inflammatory signalling (JNK)

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11
Q

Adipose tissue inflammation INDIRECT affect on muscle insulin sensitivity

A

Metabolically dysfunctional adipose leads to inflammation, which promotes ectopic lipid deposition.

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12
Q

Adipose tissue inflammation DIRECT affect on muscle insulin sensitivity

A

-TNFα infusion for 1hr increased p-JNK and serine
phosphorylation of IRS1
- TNFα infusion over 3 hours showed a repression of
insulin signalling pathway intermediates (activated
IRS1 & phosphorylated AS160

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13
Q

Active and Inactive forms of IRS1

A

– Tyrosine phosphorylation of IRS1 = ACTIVE IRS1
– Serine phosphorylation of IRS1 = INHIBITED IRS1

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14
Q

What can cause an accumulation of lipid in muscle? (2)

A

1) increased fat uptake and/or 2) reduced fat oxidation

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14
Q

Things that can influence (both directly and indirectly)
fat levels in muscle(6)

A

– Increased NEFA due to lipolysis of adipose tissue TAG stores.
– VLDL production in the liver and delivery of TAG to the muscle.
– Transport of NEFA across the sarcolemma (muscle plasma membrane).
– Lipolysis of muscle TAG stores.
– Transport of fatty acids into mitochondria for β-oxidation (i.e.,mitochondrial activity).
– Mitochondrial number.

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15
Q

NEFA transported in blood bound to

A

albumin

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16
Q

3 key players in fatty acid (FA) transport

A

-FAT/CD36 (fatty acid translocase)
-ABPpm (fatty acid binding protein, plasma membrane)
-FATP4 (fatty acid transport protein)
*Least characterized of fatty acid transporters.

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17
Q

Overexpression of which transporter lead to the greatest increase in fat uptake into muscle

A

FAT/CD36

18
Q

FAT/CD36 KO mice (4)

A

-increase in circulating fatty acids
-reduced fatty acid transport into muscle
-reduction in TAG,DAG, and ceramides
-cause muscle to become on glucose for energy productiion

19
Q

Does FAT/CD36 KO mice show evidence of compensation from other transporters

A

no

20
Q

FAT/CD36 and obesity relationship

A

Obesity and type 2 diabetes are associated with increased fat uptake into muscle due to higher levels of FAT/CD36 on the plasma membrane

21
Q

Exercise and FAT/CD36 relationship

A

Exercise increases
FAT/CD36 protein levels
and fatty acid uptake into
muscle

22
Q

AMPK: what is it and how is it activated

A

AMP- activated protein kinase
-from increased AMP/ATP ratio during exercise

23
Q

Exercise and GLUT4 relationship

A

Exercise and insulin
increase glucose uptake
by increasing GLUT4
levels at the plasma
membrane

24
Q

What does AMPK do

A

-increase glucose uptake, fatty acid uptake, fatty acid oxidation, activation of PGC-1α and PPARs
-decrease fatty acid synthesis, protein snthesis, DAG and ceramides

25
Q

Exercise and FAT/CD36 levels relationship

A

Increases FAT/CD36 levels, (increases fatty acid uptake)
-stored as TAG rather than reactive lipids (DAGS, ceramides)

26
Q

What does the mitochondria produce and how

A

produce energy by oxidizing carbohydrates, fat, and amino acids in the TCA cycle

26
Q

What has to happen before the mitochondria can produce energy

A

Fatty acids must be broken down into acetyl-CoA via β-oxidation first

27
Q

CPT1

A

Marker of mitochondrial function

28
Q

Citrate Synthase

A

Marker of mitochondria content/function

29
Q

Mt DNA

A

another marker of mitochondria content

30
Q

What does a change in CPT1 levels, but no change in citrate synthase or mtDNA suggest

A

a change in mitochondrial function without changing mitochondrial number

31
Q

What does a change in CPT1 levels and citrate synthase (or mtDNA) levels suggest

A

a change in mitochondrial content/number is driving the change in mitochondrial function

32
Q

CPT1 and citrate synthase activity with obesity

A

CPT1 - reduced (less fat taken up, less function)
Citrate synthase - reduced (fewer mitochondria)

33
Q

Two types of mitochondria that exists in muscle

A
  1. Subsarcolemmal (SS)
  2. Intramyofibrillar (IMF)
34
Q

what does Subsarcolemmal (SS) synthesize ATP for

A

energy-consuming functions at the cell surface

35
Q

what does intramyofibrillar (IMF) synthesize ATP for

A

muscle contraction

36
Q

mitochondrial content (mtDNA) and ETC activity with obesity and T2D

A

-mitochondria content reduced in obese and T2D
-ETC activity reduced, more greatly reduced in T2D
seen in SSM

37
Q

IR offspring and mitochondrial content

A

IR offspring of parents with T2D have reduced mitochondrial content, suggesting this may predispose offspring to T2D later in life

38
Q

2 important regulators of mitochondrial biogenesis

A

PGC-1α and Tfam
–> Exercise (via AMPK) increases PGC-1α
and mitochondrial conten

39
Q

strong over-expression of PGC-1α impacts

A

increases FAT/CD36 at the membrane (meaning increased lipid accumulation into the muscle) and leads to insulin resistance

40
Q

modest increase of PGC-1α

A

-increased mitochondrial content
-reduced TAG,DAG,ceramides
-increase fat oxidation at subsarcolemmal mitochondria
-increase glu uptake (increase GLUT 4 protein levels)
-Akt and AS160 increase w ins-stim

41
Q
A