Human Muscle Atrophy

Question 1

Two step process of degradation of muscle sarcomere?

Answer 1

1) Calpains (Ca dependent proteases) disassemble the sarcomere at the Z-line (by digesting Z-line proteins such as nebulin and fodrin) and break it up in smaller pieces.
2) Myosin, actin and other proteins are then digested by the ATP- ubiquitin-dependent 26S proteasome (Can’t digest connected proteins).

In addition: some proteins also degraded by cathepsins, which are located in lysosomes. Proteases from mast cells (immune cells) can also contribute to skeletal muscle breakdown.

Question 2

Ubiquitin and how it works?

Answer 2

Sarcomere broken up at the Z-disc by calpains.

Proteins then ubiquitinated (attached to the protein, ubiquitin) in an ATP-dependent reaction involving ubiquitin ligases (E1-E3). Ubiquitinated proteins are then digested by the 26S proteasome.

E3 ligases connect ubiqitins to proteins selected for breakdown

Upregulation of E3 ligases such as MAFbx and MuRF1 is a mechanism for increasing the rate of protein breakdown in muscle

Question 3

Types of physiological atrophy? (Muscles getting smaller)

Answer 3

1) μG- disuse “plus”
2) Bed rest- disuse
3) Cast immobilisation- disuse
4) High altitude- hypoxia

Question 4

Types of pathological atrophy? (Muscles getting smaller?

Answer 4

1) Starvation/malnutrition- Energy deficit
2) Cachexia (Cancer/ HIV/ ITU)- Inflammation
3) Chronic Heart Failure
4) Denervation (lession)- spinal cord injury
5) Muscle diseases- e.g. muscular dystrophies
6) Sarcopenia- Ageing (sedentary) (sarcopenia)

Question 5

What happens to muscles in space?

Answer 5

• Numerous studies (each with a small sample size!).
• Muscle strength and power decline
• Muscles atrophy (individual cells get smaller)
• The postural muscles are affected most

Specific force loss occurs in astronauts after space flight

Question 6

Starvation and muscle?

Answer 6

• Skeletal muscle lost during starvation depends upon: 1) amount of energy in the body at the outset, 2) the length of starvation.
• Generally, energy is preferably derived from carbohydrates and fat whereas muscle and brain fat are conserved.
• Fasting reduces protein synthesis in skeletal muscle and feeding doubles protein-synthesis in fasted men (Rennie et al. 1982).
• The effect of fasting and re-feeding depends on the length of the fasting period and the amount of energy available from other sources (adipose tissue, glycogen).

Carbohydrates > fat > muscle protein > brain fat, protein

Question 7

What is cachexia and what are its effects?

Answer 7

• The loss of muscle cannot be reversed by ↑ nutritional intake.
• TNFalpha and other pro-inflammatory cytokines (e.g. Interleukin-1, Interleukin-6) are ↑ in disease states associated with a loss of muscle mass. In addition, a so-called proteolysis-inducing factor (PIF) is released in several forms of cancer.
• Disease states with a rise in pro-inflammatory cytokines are: sepsis rheumatoid arthritis, Aids/HIV, burns, pancreatitis, heart failure, renal failure, and some forms of cancer.
• A moderate increase in pro-inflammatory cytokines is also often seen in (sedentary) ageing (“inflamageing”)

Question 8

Mechanism of cachexia?

Answer 8

TNFα via its receptors activates the nuclear factor-kB (NF-kB) pathway.

When phosphorylated, IkB detaches from NF-kB which translocates into the nucleus and binds to kB enhancers.

This increases the expression of the proteolytic machinery
- actions of TNFα and NF-kB are not fully understood

Question 9

Changes in body composition in aging sarcopenia?

Answer 9

Ageing sarcopenia leads to a change in body composition.

The relative contribution of fat and non-muscle fat free mass increases whereas the contribution of muscle decreases.

This causes a power deficit for the same torque.

Decrease motor unit number & increase motor unit size

However aging studies are contaminated as many ppl used are very inactive which affects health further than it should. Confounds our understanding of inherent biological ageing process.

Question 10

Factors associated with sarcopenia?

Answer 10

• Changes in circulating “anabolic” hormones – (less e.g.GH/IGF-I,Testosterone,etc)
• Metabolic dysregulation – (increase reactive O2 species)
• Inflammation (“inflamageing”) – (more degradation)
• “Anabolic resistance” to feeding and exercise – (less protein synthesis)
• less regeneration from exercise induced damage – (compromised satellite cell behaviour?)

Question 11

Effects of spinal cord injury?

Answer 11

Atrophy+ Slow→ Fast phenotype switch

Therefore oxidative to glycolytic switch

Decline in mass and quality of muscle