Module 9: Muscle Role in Metabolic Complications

Question 1

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

Answer 1

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.

Question 2

What is ectopic lipid accumulation

Answer 2

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

Question 3

Increased NEFA release from adipose tissues causes:

Answer 3

Increased fat deposition in other tissues (muscle, liver)

Question 4

IMCL (intramyocellular lipid) is positively corrrelated with

Answer 4

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

Question 5

IMCL is inversely coorelated with

Answer 5

Insulin sensitivity

Question 6

Athlete’s Paradox

Answer 6

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

Question 7

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

Answer 7

-TAG
-DAG
-Ceramides

Question 8

Over-expression of DGAT1: (increases w exercise)

Answer 8

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

Question 9

Reducing DAG improves:

Answer 9

-glucose tolerance
-insulin sensitivity

Question 10

Increasing GLUT4 at membrane affect:

Answer 10

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

Question 11

Adipose tissue inflammation INDIRECT affect on muscle insulin sensitivity

Answer 11

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

Question 12

Adipose tissue inflammation DIRECT affect on muscle insulin sensitivity

Answer 12

-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

Question 13

Active and Inactive forms of IRS1

Answer 13

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

Question 14

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

Answer 14

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

Question 14

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

Answer 14

– 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.

Question 15

NEFA transported in blood bound to

Answer 15

albumin

Question 16

3 key players in fatty acid (FA) transport

Answer 16

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

Question 17

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

Answer 17

FAT/CD36

Question 18

FAT/CD36 KO mice (4)

Answer 18

-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

Question 19

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

Answer 19

no

Question 20

FAT/CD36 and obesity relationship

Answer 20

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

Question 21

Exercise and FAT/CD36 relationship

Answer 21

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

Question 22

AMPK: what is it and how is it activated

Answer 22

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

Question 23

Exercise and GLUT4 relationship

Answer 23

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

Question 24

What does AMPK do

Answer 24

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

Question 25

Exercise and FAT/CD36 levels relationship

Answer 25

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

Question 26

What does the mitochondria produce and how

Answer 26

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

Question 26

What has to happen before the mitochondria can produce energy

Answer 26

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

Question 27

CPT1

Answer 27

Marker of mitochondrial function

Question 28

Citrate Synthase

Answer 28

Marker of mitochondria content/function

Question 29

Mt DNA

Answer 29

another marker of mitochondria content

Question 30

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

Answer 30

a change in mitochondrial function without changing mitochondrial number

Question 31

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

Answer 31

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

Question 32

CPT1 and citrate synthase activity with obesity

Answer 32

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

Question 33

Two types of mitochondria that exists in muscle

Answer 33

1. Subsarcolemmal (SS) 2. Intramyofibrillar (IMF)

Question 34

what does Subsarcolemmal (SS) synthesize ATP for

Answer 34

energy-consuming functions at the cell surface

Question 35

what does intramyofibrillar (IMF) synthesize ATP for

Answer 35

muscle contraction

Question 36

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

Answer 36

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

Question 37

IR offspring and mitochondrial content

Answer 37

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

Question 38

2 important regulators of mitochondrial biogenesis

Answer 38

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

Question 39

strong over-expression of PGC-1α impacts

Answer 39

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

Question 40

modest increase of PGC-1α

Answer 40

-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