23. Muscle atrophy Flashcards
Acute muscle wasting in critical illness
in 10 days, patients lose about 20% of their muscle CSA In critical illness, inflammation almost always assoc. with organ failure. Bigger inflamm response = more tissue loss (greater decline of up to 30% CSA lost whilst in ICU)
What happens in ICU patients?
Very rapid and severe loss of muscle in ICU patients.
Measuring muscle protein degradation
Measuring protein breakdown using tracers is difficult, hence researchers rely on surrogate measures and measurement of activity of catabolic pathways. Use of a complicated FBR formula (1% variation in initial measurement can lead to 15% variance by end of formula use)
Resistance exercise and protein synthesis
Protein synthesis is increased to a greater extent than breakdown during post-exercise recovery.
Measurement of protein breakdown using A-V balance
Infused labelled AA in arterial blood, measure at same time in arterial and venous blood and calculate difference to see if AA is taken up or released.
What is 3-Methylhistidine? and how can it be used as a measure of protein breakdown?
3-MH is a component of the two main skeletal muscle contractile proteins, myosin and actin. Urinary 3-MH excretion and plasma 3-MH concentration measurements are not a good marker of muscle protein breakdown as they can also arise from different tissues. (ie. if you eat meat).
Describe protein breakdown at a cellular level
Proteolytic systems:
- autophagy & lysosomes
- ubiquitin-proteosome system
- accounts for ~80% of total protein breakdown
- proteins selected for degradation are conjugated to ubiquitin and transported to large proteasomes
- Calpains
- Ca2+ activated
- initiate degradation of myofibrillar proteins (except actin, MHC)
- Caspases
- activated by ROS, Ca2+
- can cleave actomysin and cytoskeleton proteins
What is autophagy?
The physiological process that the cell uses to transport organelles to the lysosome for breakdown.
- an efficient method of recycling damaged and aged organelles & accumulated protein aggregates
- efficient to breakdown protein and glycogen to meet energy requirements in other tissues
- intestinal lining turnover 100% / day
- muscle 1% / day
What regulatory signalling pathways are involved in autophagy?
mTOR - inhibition of autophagy 10%
FoxO3 - stimulation of autophagy 50%
(particularly nuclear FoxO3)
Describe process of autophagy during fasting.
(ie. damaged mt needs removal)
Reduction in insulin and IGF-1
⇒Reduces activity of Akt & mTOR
⇒increases formation of autophagolysosome
⇒encapsulates mt and brings to lysosome
How do defects in autophagy lead to myopathy?
Original hypothesis = stimulate mTOR ⇒ massive increase in protein synthesis so that must result over long time in massive gains in muscle
HOWEVER
doesn’t happen because when you stimulate mTOR, which inhibits autophagy, hence get accumulation of non functional protein aggregates
ie. DMD = hyperactivity of Akt and mTOR, reduced amount of autophagy
What is ubiquination?
Way for cell to label particular proteins that need to be broken down (by autophagy or proteasome)
Ubiquitin-proteosome system
Protein is labelled with ubiquitin chain that is recognised by proteasome (E1, E2, E3 involved)
26S proteasome made up of 19S complex and 20S core proteasome.
Regulation of protein breakdown & examples of E3s.
What E+(number) ligases do we have and what structure are they in?
E1, E2 and E3 ligases.
They are in hierarchical structure.
500 different E3 ligases which all recognise a specific substrate, hence target different specific proteins for degradation.
Cross-talk between protein synthesis & breakdown pathways
If you modulate atrogin pathway, also modulate eIF3 pathway (cross-talk).
Activation of atrogin-1 (MAFbx) reduces the capacity of the protein synthetic machinery by increasing breakdown of eIF3-f, therefore reducing activity of anabolic pathway.
*Changing expression of MyoD, changes rate of proliferation.
*eIF3-f is important initiation factor in translation initiation.
