Skeletal Muscle in Disease Flashcards
What is the connection between myostatin and AIDS?
Small amounts of the protein can be detected in the circulation of adult humans, and it has been reported that the amount is raised in AIDS patients who show muscle wasting
Discuss DMD pathophysiology in terms of satellite cells
differentiated skeletal muscle cells are damaged because of a genetic defect in the cytoskeletal protein dystrophin.
As a result, satellite cells proliferate to repair the damaged muscle fibers.
This regenerative response is, however, unable to keep pace with the damage, and the muscle cells are eventually replaced by connective tissue, blocking any further possibility of regeneration.
A similar loss of capacity for repair seems to contribute to the weakening of muscle in the elderly.
What is the effect of muscular dystropht on the ability of satellite cells to proliferate?
the satellite cells are constantly called upon to proliferate, their capacity to divide may become exhausted as a result of progressive shortening of their telomeres.
What is the mechanism of damage in DMD?
- lack of the protein dystrophin (helps the thin filaments of myofibrils bind to the sarcolemma)
- Without sufficient dystrophin, muscle contractions cause the sarcolemma to tear, causing an influx of Ca++, leading to cellular damage and muscle fiber degradation.
- Over time, as muscle damage accumulates, muscle mass is lost, and greater functional impairments develop.
What is the inheritance of DMD?
abnormality of X chromosome, primarily in males
When is DMD usually diagnosed?
Early childhood
Describe the progression of symptoms of DMD
- usually first appears as difficulty with balance and motion
- then progresses to an inability to walk
- continues progressing upward in the body from the lower extremities to the upper body, where it affects the muscles responsible for breathing and circulation.
- ultimately causes death due to respiratory failure
What is the life expectancy of those with DMD?
those afflicted do not usually live past their 20s
List therapies for DMD
Cell therapy Gene therapy Transplantation into patient (iPS) Proteasome inhibitor Antibody blockade Upregulating therapy Chimaeraplast Antisense oligonucleotides
Describe DMD cell therapy
Transplant directly intramuscularly stem cells or myoblasts which can come from the patient (so they need genetic modification) or from a healthy donor (can be injected directly into muscle)
Describe DMD gene therapy
Viruses or plasmids can be used to target the cytoplasm organelles or the nuclear level via DNA or RNA modification
Describe DMD iPS transplant
- Isolate any cell from DMD patient (eg. fibroblast)
- Reprogramme it to iPS cell
- Correct the gene
- Differntiate into myogenic cell
- Transplant into patient
Describe proteasome inhibitor for DMD
Drugs such as Velcade block proteasomes which break down dystrophin
Describe DMD antibody blockade therapy
Glucocorticoids currently used to treat DMD are not very effective
IL-6 blockade may be helpful (decrease myofibre necrosis) but some studies show that this actually increases inflammation
Describe DMD upregulation therapy
In mice overexpression of utrophin, the autosomal paralogue of dystrophin as a transgene in mdx mice has show in can prevent muscle pathology
