Lecture 21 - Mechanisms of atrophy Flashcards
Muscle wasting in the ICU leads to…
ongoing impaired performance
The amount of organ failure the patient will positively influence the amount of…
muscle wasting that is observed
What are some the ways of potentially reducing muscle wasting in critical illness?
Electrical muscle stimulation
Functional electrical stimulations with cycling
true or false
Protein synthesis and degradation are never the same throughout the day
true
protein synthesis is very responsive to the intake of protein
protein degradation follows the same balance but not to the same extent
What is the surrogate measure for protein breakdown?
examine the incoming protein concentration in the plasma
compare to outgoing (venous) concentration of plasma
the different accounts for the breakdown/absorption from the muscle
Can also inject a stable isotope, if there is unlabelled proteins in addition to the labelled ones- there is protein breakdown
What happens to muscle protein levels during prolonged knee-extensor exercise in humans
muscle protein is lost
metabolised
What is 3 -methylhistidine (3-MH) a component of?
the two min skeletal muscle contractile proteins - myosin and actin
True or False
Urinary 3-MH excretion and plasma 3-MH concentration measurements provide accurate markers of muscle protein breakdown
False
they can also arise from different tissues
Which proteolytic system accounts for 80% of total protein breakdown?
Ubiquitin-proteosome system
proteins selected for degradation are conjugeated to ubiquitin then transported to large proteasomes
How are Calpains activated?
Ca2+ activated
initiate degradation of myofibrillar proteins (except actin, MHC)
How are Caspases activated?
Activated by ROS, Ca2+
Can cleave actomysoin and cytoskeleton proteins
what is Autophagy?
An efficient moethod of recycling damaged and aged orgranelles and accumulated proteins aggregates
An efficient method to breakdown protein and glycogen to meet the energy requirements in other tissues
Autophagy is the physiological process that the cell uses to transport organelles to the lysosome for breakdown
What are the steps of autophagy?
Vescicle nucleation
Vescicle elongation
formation of that Autophagosome
Lysosome fuses and adds lysosomal hydrolase to the Autophagosome
Autolysosome is formed
vescicle breakdown and degradation begins
factors are released and used into the cell or transported elsewhere
What regulatory signalling pathways are involved in regulating autophagy and what are their effects
mTOR - inhibition of autophagy (10%)
Fox03 - stimulation of autophagy (50%)
If you stimulate autophagy you get…
what about if you reduce it?
a muscle wasting disease
reduction in autophagy also results in muscle wasting disease
poly-ubiquinated proteins are recognised by the _____ and broken down
proteasome
In skeletal muscle there are multiple E3 ligases including
atrogen-1/MAFbx
MURF-1
These are upregulated in wasting conditions
In skeletal muscle there are multiple E3 ligases (atrogenes) including
atrogen-1/MAFbx
MURF-1
These are upregulated in wasting conditions
if FOXO is phosphrylated in moves ___ the nucleus and therefore cannot stimulate the transcription of MURF-1 and Atrogen
out of the cell
An increase in MURF -1 / Atrogen -1 protein levels causes…
and increase in protein ubiqiunation and hence, an increase in protein degradation
what is an example of cross-talk between protein synthesis and breakdown pathways
Atrogen has specific targets that are main contributors to the increase in protein synthesis
What are MAFbx’s two actions?
decreases MyoD (Very important in myoblasts and proliferation) - there this causes a reduction in the number of cells
other target is e1F3-f (one of the main componenets of a complex that allows further further activation of S6K = reduced protein synthesis
True or false
Activation of atrogen-1 reduces the capacity of the protein synthetic machinery
true
the initiation factor eIF-f is a major target for Atrogen1/MAFbx function in skeletal muscle atrophy
Caspase _ and _ play a key role in programmed cell death / apoptosis
3 and 9
which caspase plays a key role in the regulation of inflammation?
caspase 1
Exercise acutely increases protein breakdown to enhance remodelling and remove …
damaged proteins
