L7.3 Atrophy

Question 1

Muscle wastage in ICU?

Answer 1

• Muscle wasting rapid and severe in ICU → ↓ muscle performance Disuse results in transition of fibres from slow → fast (I → IIA → IIB)

Question 2

How is protein breakdown measured?

Answer 2

• * Through the dye method
• * Sample blood from A (delivers protein to muscles) & V (collect broken down proteins from muscles)
• * Protein synthesis (greater) & breakdown (less) occurs during post-exercise recovery 3-methylhistidine → component of contractile protein, myosin & actin
• * Not an accurate marker of protein breakdown, broken down protein may arise from different tissues

Question 3

Hyperglycaemia on muscles?

Answer 3

Hyperglycaemic patients → may have detrimental effects on muscles

Question 4

What is muscle wastage due to?

Answer 4

* Muscle wastage due to mismatch between anabolic & catabolic protein metabolism

Question 5

Protein breakdown: Autophagy

Answer 5

• * Transports organelles to lysosomes for breakdown
• * Recycles damage & aged organelles
• * Efficient way to breakdown large amount of proteins
• * Could also breakdown glycogen → to meet energy requirements in other tissues
• * Defects: could arise from both additional stimulation or lack of stimulation → muscle wastage

Question 6

Mechanims of autophagy

Answer 6

* Vesicle nucleation → vesicle elongation → docking & fusion → Vesicle breakdown & degradation

Question 7

Regulation of autophagy

Answer 7

• * mTOR (anabolic) → inhibits autophagy (10%)
• * Foxo3 (catabolic) → stimulates autophagy (50%)

Question 8

Protein breakdown: Ubiquitin proteosome systems

Answer 8

• * Responsible for 80% of protein breakdown
• * E3-ligases (couples ubiquitin to substrates) → tags proteins → recognised → then broken down
  
  • * 1 or 2 E1 ligases, a couple E2 ligases, ~200 E3 ligases

Question 9

Important E3-ligases

Answer 9

• Atrogin-1/MURF-1
  
  • * Activation → ↓capacity of protein synthetic machinery Regulated by Foxo (which is regulated by AKT - also regulates mTOR - by phosphorylation)
  • * Foxo → ↑MURF-1/atrogin transcription → ↑MURF-1/Atrogin-1 protein levels → Protein ubiquination → ↑ Protein degradation
• MAFbx
  
  • * Inhibits eIF3-f → ↓protein synthesis
  • * Inhibits MyoD → ↓proliferation

Question 10

Protein breakdown: Caspases & Calpains

Answer 10

Caspses (responds to Ca2+ & ROS) - cleaves cytoskeleton

• * Caspases 3&9 → DNA cleavage → Key role in apoptosis
• * Caspases 1 → cleaves inactivated cytokines → induce other cytokines → key role in regulation of inflammation

Calpains (Responds to Ca2+)

• Degrades myofibrillar proteins & MyHC