Muscle and Muscular Dystrophy

Question 1

Three types of muscle

Answer 1

1) skeletal
2) cardiac
3) smooth

Question 2

What do all types of muscle move by?

Answer 2

myosin + actin

Question 3

skeletal muscle key features

Answer 3

long, multinucleated cells= muscle fibers –> cells at the periphery

largest type

striated (has sarcomeres–> can see A band, I band, etc. )

If connected to CT… CT stains blue

NOT branched

Question 4

cardiac muscle key features

Answer 4

nuclei in middle (1-2 per cell)
cells more rounded
have intercalated discs that connect adjacent cells (looks squiggly)

Question 5

smooth muscle key features

Answer 5

NO striation so look smooth lol, when smooth muscle contracts, the nuclei will spiral, kink, or twist, leading us to smooth muscle

once central nuclei that looks squiggly normally

tightly packed

surrounded by reticular fibers

elaborate in intermediate filaments, thick > thin

Question 6

What is a sarcomere?

Answer 6

repeating unit of a microfibril and microfibrils make up muscle fiber aka cell

Question 7

components of a sarcomere

Answer 7

A band= dark, thick filaments, myosin

I band= white, thin filaments, actin

Z-line/ Z-disc is the dark line bisecting I band

M line is the line bisecting A band

sarcomere goes Z disc to Z disc

Question 8

A band

Answer 8

thick filaments, has myosin, dark band

Question 9

I band

Answer 9

thin filaments, has actin, light band

Question 10

M line

Answer 10

in the middle of the A band

where thick filaments are cross linked

Question 11

Z line

Answer 11

at the end of each sarcomere

has alpha- actinin anti parallel dimer–> each end has actin, crosslinking of thin filaments

Question 12

cardiomyopathies

Answer 12

cardiac muscle diseases associated with mechanical and electrical dysfunction

50% have family history –> usually autosomal dominant

often mutations in SARCOMERIC PROTEINS

Question 13

Fundamentals of thick filaments

Answer 13

in striated muscle
rods
bipolar
myosin composition

in non muscle cells:
small rods
less myosin molecules
still bipolar

Question 14

Structure of myosin

Answer 14

asymmetric

2 globular heads attached to rods

rod= hexamers of 6 polypeptides 2 heavy, 2 pairs of light chains aka 4)

Head binds actin + ATPase

rods assemble into thick filament

Question 15

Fundamentals of thin filaments including composition

Answer 15

polymer of G - actin = F - actine
2 intertwined actin monomers with helical pattern

have tropomyosin and troponins

• end at middle of A band
  + end at Z line

Question 16

troponin subunits (3)

Answer 16

I, C, T

inhibitory: inhibit myosin-actin interaction
calcium: when calcium binds it removes the inhibition
tether: theres C+ I to tropomyosin

Question 17

Sliding filament mechanism

Answer 17

neither thin or thick filaments change length…. instead the thin filaments on either side slide inwards = greater overlap of thick filaments

muscle contracts by conformation change in myosin head coupled with ATP hydrolysis to attachment and pulling on actin thin filaments

Question 18

Excitation-contraction coupling

Answer 18

electrical stimulus arrives at NMJ–> release ACh to NMJ–> Na 2+ channels open= action potential along T tubule–> Ca2+ released from sarcoplasmic reticulum (SR) –> Ca2+ binds troponin C= conformation change in tropomyosin= myosin heads can bind = thin/thick filament interactions leads to muscle contraction

Question 19

How are actin and myosin regulated by free Ca2+?

Answer 19

Actin (aka thin filament) based regulation:
Ca 2+ release–> regulation above

Myosin (aka thick filament) based regulation:
Ca2+ activates kinase and then it phosphorylates myosin–> makes myosin more active

Question 20

Where do T-tubules attach and what happens?

Answer 20

attaches to sarcoplasmic reticulum (SR) and then it releases Ca2+ from Ca2+ release channels (ryanodine receptors)

Question 21

Titin

Answer 21

largest polypeptide
restore overlap of sarcomere so it can return to its resting length after contraction

I band portion= free as a molecular spring

terminus anchored at Z discs and M lines

Question 22

costameres

Answer 22

type of intermediate filament that attach myofibrils to cell membrane at Z disc… have integrin

Question 23

what do intermediate filaments do in relation to muscle

Answer 23

3D network connecting all components of muscle cell together

maintains structural integrity….

Question 24

5 types of muscular dystrophy

Answer 24

Emery-Dreifuss MD

Myotonic MD

Duchenne’s(DMD) / Beckers (BMD) (Dystrophinopathies)

Fascioscapulohumeral MD (FSH)

Limb girdle MD (LGMD)

Question 25

key characteristics of emery-dreifuss MD

Answer 25

slowly progression muscular wasting in upper arms and lower legs, contractures, cardiac abnormalities that increase risk of sudden cardiac arrest and death

important of diagnosing early and inserting pacemaker

Question 26

mutations in emery dreifuss

Answer 26

nuclear envelope:
Emerin: X linked
Lamin A: autosomal dominant

part of LINC complex connecting nuclear lamina to cytoskeleton

Question 27

most common form of muscular dystrophy in adults

Answer 27

myotonic dystrophy

Question 28

key characteristics of myotonic dystrophy

Answer 28

genetic anticipation
variable symptoms and age of onset
autosomal dominant
affects multiple symptoms / organs

Question 29

genetic effect in myotonic dystrophy

Answer 29

repeat expansion of 3/4 nucleotide repeats

expansion of a trinucleotide repeat CTG or CCTG

Question 30

genetic anticipation

Answer 30

with each generation, there is an increase in disease severity and decrease in age of onset

(CTGs increase with each generation)

Question 31

Why does repeat expansion of nucleotide repeats cause MD?

Answer 31

RNA toxicity

expansion of CT, CCTG–> causes abnormal hairpin structure to form in nucleus and therefore it can not be exported from the nucleus to the cytoplasm

also, there is sequestering of splicing factors

results in spliceopathy

Question 32

Key characteristics of Dystrophinopathies

Answer 32

X linked recessive

33% LACK family history, 66% inherited

mutations in DYSTROPHIN gene causes duchennes and beckers

Question 33

Duchennes MD

Answer 33

DMD
severe
intellectual disabilities
lot of stuff from birth, wheelchair by 12, death by 25

OUT OF FRAME DELETIONS–> premature stop codons

Question 34

Beckers MD

Answer 34

BMD
mild
symptoms later
may walk until later in life
NO intellectual disabilities

IN FRAME DELETIONS–> smaller but functional dystrophin

Question 35

Dystrophin

Answer 35

largest human gene with lots of isoforms

has 4 regions

located just under muscle cell membrane

NOT FOUND in DUCHENNES MD

Question 36

Dystrophin can be in complex with other proteins know as….

Answer 36

DAPC

creates structural and mechanical support and signal transduction

Question 37

What does electromicrograph look like for skeletal muscle of DMD pt?

Answer 37

has center nuclei which is a hallmark of regeneration

Question 38

Fascioscapulohumeral MD (FSH) charachteristics

Answer 38

third most common 
autosomal dominant
genetic anticipation 
initially present w weakness of face and shoulders 
only 20% in wheelchair

Question 39

mutations for FSH

Answer 39

heterozygous deletion in chromosome near telomere

type 2 shows heterozygous mutuation in thing required for DNA methylation

Question 40

Characteristics of Limb Girdle MD (LGMD)

Answer 40

dominant= type 1 
recessive= type 2 

often diagnosed after others are excluded

> 16 gene mutations encoding muscle proteins

Question 41

In MD the number of (a) cells decreases which shows the (b) capacity is limited

Answer 41

a) satellite

b) regenerative

Question 42

intercalated discs

Answer 42

are specialized junctions within the cardiac muscle

*They serve as a terminal “Z” line for cells

Question 43

Endomysium

Answer 43

connective tissue that covers each single muscle fiber AKA muscle cell