Module 9: Muscle Role in Metabolic Complications Flashcards
3 pathways that have been implicated in the
development of insulin resistance in skeletal
muscle
- Ectopic lipid accumulation leading to lipotoxicity.
- Pro-inflammatory cytokines from adipose tissue that travel to the muscle.
- Recruitment of pro-inflammatory macrophages directly into muscle.
What is ectopic lipid accumulation
significant accumulation of fat in tissues where it should not be stored
Increased NEFA release from adipose tissues causes:
Increased fat deposition in other tissues (muscle, liver)
IMCL (intramyocellular lipid) is positively corrrelated with
BMI, waist-to-
hip ratio, and % body fat
IMCL is inversely coorelated with
Insulin sensitivity
Athlete’s Paradox
High IMCL, high insulin sensitivity. high oxidative capacity, high muscle TAGS
Obesity is associated with an increase of: (3 answers)
-TAG
-DAG
-Ceramides
Over-expression of DGAT1: (increases w exercise)
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
Reducing DAG improves:
-glucose tolerance
-insulin sensitivity
Increasing GLUT4 at membrane affect:
-improve glucose uptake
-improve insulin sensitivity
-reduce inflammatory signalling (JNK)
Adipose tissue inflammation INDIRECT affect on muscle insulin sensitivity
Metabolically dysfunctional adipose leads to inflammation, which promotes ectopic lipid deposition.
Adipose tissue inflammation DIRECT affect on muscle insulin sensitivity
-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
Active and Inactive forms of IRS1
– Tyrosine phosphorylation of IRS1 = ACTIVE IRS1
– Serine phosphorylation of IRS1 = INHIBITED IRS1
What can cause an accumulation of lipid in muscle? (2)
1) increased fat uptake and/or 2) reduced fat oxidation
Things that can influence (both directly and indirectly)
fat levels in muscle(6)
– 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.
NEFA transported in blood bound to
albumin
3 key players in fatty acid (FA) transport
-FAT/CD36 (fatty acid translocase)
-ABPpm (fatty acid binding protein, plasma membrane)
-FATP4 (fatty acid transport protein)
*Least characterized of fatty acid transporters.
Overexpression of which transporter lead to the greatest increase in fat uptake into muscle
FAT/CD36
FAT/CD36 KO mice (4)
-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
Does FAT/CD36 KO mice show evidence of compensation from other transporters
no
FAT/CD36 and obesity relationship
Obesity and type 2 diabetes are associated with increased fat uptake into muscle due to higher levels of FAT/CD36 on the plasma membrane
Exercise and FAT/CD36 relationship
Exercise increases
FAT/CD36 protein levels
and fatty acid uptake into
muscle
AMPK: what is it and how is it activated
AMP- activated protein kinase
-from increased AMP/ATP ratio during exercise
Exercise and GLUT4 relationship
Exercise and insulin
increase glucose uptake
by increasing GLUT4
levels at the plasma
membrane
What does AMPK do
-increase glucose uptake, fatty acid uptake, fatty acid oxidation, activation of PGC-1α and PPARs
-decrease fatty acid synthesis, protein snthesis, DAG and ceramides
Exercise and FAT/CD36 levels relationship
Increases FAT/CD36 levels, (increases fatty acid uptake)
-stored as TAG rather than reactive lipids (DAGS, ceramides)
What does the mitochondria produce and how
produce energy by oxidizing carbohydrates, fat, and amino acids in the TCA cycle
What has to happen before the mitochondria can produce energy
Fatty acids must be broken down into acetyl-CoA via β-oxidation first
CPT1
Marker of mitochondrial function
Citrate Synthase
Marker of mitochondria content/function
Mt DNA
another marker of mitochondria content
What does a change in CPT1 levels, but no change in citrate synthase or mtDNA suggest
a change in mitochondrial function without changing mitochondrial number
What does a change in CPT1 levels and citrate synthase (or mtDNA) levels suggest
a change in mitochondrial content/number is driving the change in mitochondrial function
CPT1 and citrate synthase activity with obesity
CPT1 - reduced (less fat taken up, less function)
Citrate synthase - reduced (fewer mitochondria)
Two types of mitochondria that exists in muscle
- Subsarcolemmal (SS)
- Intramyofibrillar (IMF)
what does Subsarcolemmal (SS) synthesize ATP for
energy-consuming functions at the cell surface
what does intramyofibrillar (IMF) synthesize ATP for
muscle contraction
mitochondrial content (mtDNA) and ETC activity with obesity and T2D
-mitochondria content reduced in obese and T2D
-ETC activity reduced, more greatly reduced in T2D
seen in SSM
IR offspring and mitochondrial content
IR offspring of parents with T2D have reduced mitochondrial content, suggesting this may predispose offspring to T2D later in life
2 important regulators of mitochondrial biogenesis
PGC-1α and Tfam
–> Exercise (via AMPK) increases PGC-1α
and mitochondrial conten
strong over-expression of PGC-1α impacts
increases FAT/CD36 at the membrane (meaning increased lipid accumulation into the muscle) and leads to insulin resistance
modest increase of PGC-1α
-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
