Muscle

Question 1

General Muscle info

Answer 1

Myofibril = fusion of myoblast = multinuc muscle cell/fiber
Cell attach/Stab = Dystrophin (sim to spectrin)
Skl M = striated connected by CT in ECM. Dystrophin links actin cytoskeleton to integral glycoprotein complex that interacts with ECM (laminin/collagen) - transduces contractile force form intracell sarcomeres to ECM

Question 2

Dystrophin interaction

Answer 2

Binds actin, dystroglycans, synaptophines, dystrobrevin. Attaches actin-cyto to PM and ECM linking actin cyto to laminin-2

Question 3

Dystroglycan complexes

Answer 3

Alpha dystroglycan - binds ECM glycoprotein (laminin) and proteoglycan (agrin)
Beta dystroglycan - binds dystrophin, other adapter proteins and intracell signal proteins (GRB2)

Question 4

Dystroglycan complex function

Answer 4

Confers structural stability during contraction. Absence = muscle fibers succesptible to dmg, loss DAP at sarcolemma and fragile sarcolemma leads to muscle degeneration

Question 5

M repair and growth

Answer 5

Satellite cells and side pop cells
Sat cells lie in Basal Lamina of mature myotubes. Stress - act myoblasts - surface of myotubes - fuse with myofibers - mature cells
Stem cells = Side pop, in bone marrow/skel M wall. Diff into haematopocite and Sat cell

Question 6

Satellite Cells

Answer 6

Form regenerated M fibers after M dmg. In D repair response cannot keep up with repeated dmg leading to CT and fat accumulation
Sat cells: shortened telomers limits reproductive capacity

Question 7

Absence of dystophin and muscle destruction

Answer 7

Membrane destabalization: loss of DAP at sarcolemma - absence of phys link leading to fragile sarcolemma
Influx Ca leads to apoptosis and necrosis
Increased contraction induced injury leads to repeated degeneration and inflammation and eventual M destruction

Question 8

Muscular dystrophies

Answer 8

Genetic, Dys= weakening, degen or abnorm development, severe presents at childhood. Progressive muscle weak and atrophy increases serum creatine kinase. Diagnosis via blood test, PCR, M biopsy. Supportive treatment

Question 9

Dystrophin information

Answer 9

DMD: total loss
BMD: partial function
Largest gene, 7 promoters, 29 exons, repeat seq on introns = increased mutation
Cyto to sarcolemma-dystroglycan complex in M cells

Question 10

What are the X-linked MD’s

Answer 10

DMD, Becker MD (BMD), Em Dr MD

Question 11

DMD info

Answer 11

common and sever affecting cardiac and skl muscle (1/3.5k). 2/3 mutations from mother, 1/3 new, 10-20% mosaic
Xp21, 472kDa dys mutation - partial deletion, frameshift mutation, pt mutation - nonfunctional protein — No detectable Dystrophin in M

Question 12

Clinical DMD

Answer 12

Norm birth, weak at 3-5yrs, leg weak = Gower’s sign, waddle, lordosis and scoliosis
Atrophy - wheelchair at 10-12 yrs, M contractions, cog impairment (down 20% IQ), resp and cardiac muscle increasingly impaired. Rarely live past 20-30 yrs due to resp or cardiac fail

Question 13

DMD diagnosis

Answer 13

Increased serum creatine lvls, M biopsy = immunohistochem and western blot, PCR deletion screen

Question 14

DMD carriers

Answer 14

No clin manifestation, 8% FM heterozygous have M weakness due to reduced X-inactivation

Question 15

BMD

Answer 15

6/100k, Mut dystrophin: inframe insert/ deletion - partial function - more mild.
Onset late childhood, slow progression, variance

Question 16

Em Dr MD

Answer 16

1/100k, AD form rare, mut in Emerin or Lam A/C
Defect in Lamin (IF) assembly/attach to nuc envelope - affects stressed tissue
Onset Childhood, affects skl and cardiac M
Joint deform and decreased mobility, cardiomyopathy, conductive defects, arrythmias in adult - pacemaker by 30 - sudden cardiac fail common

Question 17

What are the autosomal MD

Answer 17

Myotonic Dystrophy, Facioscapulohumeral MD, Limb Girdle MD, Congenital MD

Question 18

Myotonic Dystrophy

Answer 18

AD, 1/8k, myotonin protein kinase disorder, tri-nuc repeat disorder (CTG)= anticipation. Multisystemic.
Onset 20-40, slow M degen and myotonia (invol contractions), weak hands legs (gait) sternomastoids, Atrophy facial M - ptosis, haggered appearance

Question 19

Facioscapulohumeral MD

Answer 19

Rare, AD, prog weak face, scap, up arms. Del of subtelometric tandem repeat (4q35 or t4q:10q)
Onset 10-40, inability to puff checks, facial weak ptosis, difficulty raising arms and winged scapula, progressive weak legs, sensorinereal hearing loss, arrythmias
Normal life expectency

Question 20

Limb Girdle MD types

Answer 20

1. LGMD1: AD, rare, adult onset, laminopathies, caveolin-3 mut (PM invag so sarcolemma membrane alteration)
2. LGMD2: AR, 10-20 yrs, Calpain (alpha, beta, gamma, epsilon sarcoglycans), titin (assoc with myosin), telethonin mutations

Question 21

Describe Sarcoglycenopathies (LGMD)

Answer 21

complex= N-glycosylated transmembrane protein (glycocalyx) linked to dystrophin via association with dystroglycan complex. Defect in assembly of sarcoglycans leads to:

1. Disrupted interactions with dystroglycan protein complex
2. Disrupted association of sarcolemma with ECM

Question 22

LGMD clin

Answer 22

similar to DMD, weak prox M, 10-20, disabled at 20-25, Differences = Psedohypertrophy and contractions rare, no cog impair

Question 23

Congenital MD

Answer 23

Onset birth, mut in laminin, gen M weak, resp insuff, contractures, seize, mental retard
Impaired myogenesis, synaptogenesis, and mechanical stability
Clinically variable

Question 24

DMD treatment

Answer 24

1. Myoblast transfer- Challeneges are Dys too large for viral vector, many cells need gene, immune rejects vector.
   In trial: Stem cell therapy with systemic delivery
   Upreg of utrophin (fetal homologue)