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.