X-linked muscular dystrophy

Question 1

What is Duchenne Muscular Dystrophy (DMD)?

Answer 1

A degenerative disorder of skeletal and cardiac muscle caused by a defective dystrophin (DMD) gene on the X-chromosome (X-linked disorder)
- leads to the loss of Dp427-M isoform of dystrophin

Question 2

What does the loss of this isoform trigger?

Answer 2

Pathophysiological alterations

Question 3

What is dystrophin?

Answer 3

Dystrophin is a large structural protein that plays a critical role in maintaining the integrity of the skeletal muscle surface membrane system (sarcolemma)

Question 4

What is the dystrophin-glycoprotein complex (DGC) composed of and what is its function?

Answer 4

• the DGC is composed of dystroglycan, sarcoglycans and syntrophins to name a few
• has mechanical stabilising and signalling roles in mediating reactions between the cytoskeleton and extracellular matrix

Question 5

What is the primary function of dystrophin?

Answer 5

to provide stability to the sarcolemma during muscle contraction by distributing the force generated by contractile proteins across the surface membrane

Question 6

How does dystrophin maintain the structural integrity of the sarcolemma?

Answer 6

by preventing the influx of calcium ions, which can trigger muscle damage

Question 7

What do mutations in the DMD gene cause?

Answer 7

Mutations in the DMD gene lead to almost complete loss of Dp427-M isoform of dystrophin

Question 8

What happens to muscle fibres in the absence of dystrophin?

Answer 8

They become more susceptible to necrosis, reactive myofibrosis and sterile inflammation

Question 9

Explain how the loss of dystrophin leads to necrosis

Answer 9

• sarcolemma loses structural support and is more prone to damage during muscle contraction
• this vulnerability leads to the influx of calcium ions into muscle fibres, activating proteolytic enzymes that cause cellular damage
• continuous cycles of muscle damage leads to fibre degeneration and necrosis

Question 10

Explain how the loss of dystrophin leads to reactive myofibrosis

Answer 10

• necrotic muscle fibres trigger a repair response involving fibroblast infiltration which leads o reactive myofibrosis
• excess collagen deposition occurs, replacing damaged muscle fibres with non-contractile scar tissue
• this further impairs muscle function and contributes to stiffness

Question 11

Explain how the loss of dystrophin leads to sterile inflammation

Answer 11

• Necrosis and myofibrosis leads to release of intracellular components which activates an inflammatory response
• immune cells invade the damaged muscle tissue, exacerbating the inflammatory response
• this chronic sterile inflammation perpetuates tissue damage and disrupts balance between tissue repair and degeneration