Lecture 21 - Mechanisms of atrophy

Question 1

Muscle wasting in the ICU leads to…

Answer 1

ongoing impaired performance

Question 2

The amount of organ failure the patient will positively influence the amount of…

Answer 2

muscle wasting that is observed

Question 3

What are some the ways of potentially reducing muscle wasting in critical illness?

Answer 3

Electrical muscle stimulation

Functional electrical stimulations with cycling

Question 4

true or false

Protein synthesis and degradation are never the same throughout the day

Answer 4

true

protein synthesis is very responsive to the intake of protein

protein degradation follows the same balance but not to the same extent

Question 5

What is the surrogate measure for protein breakdown?

Answer 5

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

Question 6

What happens to muscle protein levels during prolonged knee-extensor exercise in humans

Answer 6

muscle protein is lost

metabolised

Question 7

What is 3 -methylhistidine (3-MH) a component of?

Answer 7

the two min skeletal muscle contractile proteins - myosin and actin

Question 8

True or False

Urinary 3-MH excretion and plasma 3-MH concentration measurements provide accurate markers of muscle protein breakdown

Answer 8

False

they can also arise from different tissues

Question 9

Which proteolytic system accounts for 80% of total protein breakdown?

Answer 9

Ubiquitin-proteosome system

proteins selected for degradation are conjugeated to ubiquitin then transported to large proteasomes

Question 10

How are Calpains activated?

Answer 10

Ca2+ activated

initiate degradation of myofibrillar proteins (except actin, MHC)

Question 11

How are Caspases activated?

Answer 11

Activated by ROS, Ca2+

Can cleave actomysoin and cytoskeleton proteins

Question 12

what is Autophagy?

Answer 12

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

Question 13

What are the steps of autophagy?

Answer 13

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

Question 14

What regulatory signalling pathways are involved in regulating autophagy and what are their effects

Answer 14

mTOR - inhibition of autophagy (10%)

Fox03 - stimulation of autophagy (50%)

Question 15

If you stimulate autophagy you get…

what about if you reduce it?

Answer 15

a muscle wasting disease

reduction in autophagy also results in muscle wasting disease

Question 16

poly-ubiquinated proteins are recognised by the _____ and broken down

Answer 16

proteasome

Question 17

In skeletal muscle there are multiple E3 ligases including

Answer 17

atrogen-1/MAFbx

MURF-1

These are upregulated in wasting conditions

Question 18

In skeletal muscle there are multiple E3 ligases (atrogenes) including

Answer 18

atrogen-1/MAFbx

MURF-1

These are upregulated in wasting conditions

Question 19

if FOXO is phosphrylated in moves ___ the nucleus and therefore cannot stimulate the transcription of MURF-1 and Atrogen

Answer 19

out of the cell

Question 20

An increase in MURF -1 / Atrogen -1 protein levels causes…

Answer 20

and increase in protein ubiqiunation and hence, an increase in protein degradation

Question 21

what is an example of cross-talk between protein synthesis and breakdown pathways

Answer 21

Atrogen has specific targets that are main contributors to the increase in protein synthesis

Question 22

What are MAFbx’s two actions?

Answer 22

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

Question 23

True or false

Activation of atrogen-1 reduces the capacity of the protein synthetic machinery

Answer 23

true

the initiation factor eIF-f is a major target for Atrogen1/MAFbx function in skeletal muscle atrophy

Question 24

Caspase _ and _ play a key role in programmed cell death / apoptosis

Answer 24

3 and 9

Question 25

which caspase plays a key role in the regulation of inflammation?

Answer 25

caspase 1

Question 26

Exercise acutely increases protein breakdown to enhance remodelling and remove …

Answer 26

damaged proteins