Lecture 21 Flashcards
What are the 4 main methods of muscle breakdown?
Ubiquitin-proteasome
Autophagy
Calcium mediated protein breakdown
Atrogin and effects on anabolic signalling
What is characteristic of ICU patients with muscle wasting? (blood glucose)
ICU patients that experience muscle wasting typically have low blood glucose.
What happens to muscle mass during muscle wasting?
Muscle wasting causes very rapid loss of muscle mass.
What factors in ICU patients cause more muscle wasting?
The more organs that fail the more muscle wasting occurs.
What kind of cells can be found in muscles experiencing muscle wasting?
Lots of inflammatory cells in muscles experiencing muscle wasting.
What are some methods for measuring protein degradation?
Muscle intake of amino acids is measured and compared to degraded amino acids and this gives a general idea of the breakdown of amino acids.
Stable isotope infusion can also be used where intake concentration is measured and released concentration.
What happens to protein breakdown during post-exercise recovery?
Protein breakdown increases after post exercise recovery.
What happens to protein breakdown during intensive exercise?
During intensive exercise protein breakdown is stimulated.
Why are urinary 3-MH and plasma concentrations of 3-MH not good indicators of protein degradation?
Due to the fact that they can be derived from other tissues.
What is the most commonly used method of protein breakdown?
Ubiquitin-proteosome system.
What is the function of calpains?
Initiate degradation of myofibrillar proteins (except actin and myosin)
What degradation pathways are stimulated by calcium?
calpains
caspases (ROS also activate them)
What do caspases do?
Cleave actomyosin and cytoskeletal proteins.
What happens during autophagy?
Autophagy is an efficient method to break protein down and is characterized by transporting organelles to lysosomes for degradation.
Why is autophagy sometimes used over other methods?
autophagy degrades protein and glycogen to meet energy requirements in tissue.
How is autophagy regulated?
mTOR inhibits autophagy
FoxO3 stimulates autophagy
Why is autophagy so tightly regulated?
Defects in autophagy leads to myopathy. Too much causes wasting and too little also causes muscle wasting
Why are proteins polyubiquitinated?
poly-ubiquitinated proteins are recognised by the proteasome and broken down.
What do E3 ligases do?
E3 ligases couple ubiquitin to substrates.
How are E3 ligases so specific to so many proteins despite only being approximately 200 of them?
1 or 2 E1 ligases, a couple of E2 ligases but 200+ E3 ligases.This creates many combinations for proteins to be targetted for breakdown.
How does ubiquitination occur?
E1 couples ubiquitin to an E2 ligase and this ligase couples ubiquitin to E3 ligase which transfers it to the the polypeptide and this process is repeated until protein is polyubiquitinated.
What are some examples of muscle specific E3 ligases?
Atrogin -1 / MAFbx
MURF-1
What is FOXO?
FOXO is the regulator of transcription of MURF-1 / Atrogin - 1
What happens when FOXO is phosphorylated?
Phosphorylation of FOXO releases it from the nucleus and so it no longer stimulates MURF-1/Atrogin-1 transcription.
What does AKT phosphorylation do?
AKT phosphorylation stimulates the mTOR pathway which results in 4E-BP1 and S6KI upregulation and hypertrophy.
AKT also inhibits protein degradation by inhibiting atrogin-1 production.
*AKT phosphorylation occurs in response to anabolic signals.
How does Atrogin-1 decrease protein synthesis?
Atrogin-1 has specific targets important to protein synthesis which decreases protein synthesis.
What does Atrogin-1 do to MyoD production?
Atrogin-1 reduces MyoD production
What is the function of eIF3-F?
eIF3-f is one of the main components of a complex that allows further activation of S6KI
What does atrogin-1 activation do to protein synthesis?
Activation of atrogin-1 reduces capacity of protein synthetic machinery.
What is the role of caspase 3 and 9?
Caspases 3 and 9 play a key role in apoptosis.
What is the function of caspase 1?
Caspase 1 plays a key role in regulation of inflammation.
What is the function of S6KI?
Expression of this protein results in hypertrophy.
