Muscle and Muscular Dystrophy Flashcards
Three types of muscle
1) skeletal
2) cardiac
3) smooth
What do all types of muscle move by?
myosin + actin
skeletal muscle key features
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
cardiac muscle key features
nuclei in middle (1-2 per cell)
cells more rounded
have intercalated discs that connect adjacent cells (looks squiggly)
smooth muscle key features
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
What is a sarcomere?
repeating unit of a microfibril and microfibrils make up muscle fiber aka cell
components of a sarcomere
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
A band
thick filaments, has myosin, dark band
I band
thin filaments, has actin, light band
M line
in the middle of the A band
where thick filaments are cross linked
Z line
at the end of each sarcomere
has alpha- actinin anti parallel dimer–> each end has actin, crosslinking of thin filaments
cardiomyopathies
cardiac muscle diseases associated with mechanical and electrical dysfunction
50% have family history –> usually autosomal dominant
often mutations in SARCOMERIC PROTEINS
Fundamentals of thick filaments
in striated muscle
rods
bipolar
myosin composition
in non muscle cells:
small rods
less myosin molecules
still bipolar
Structure of myosin
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
Fundamentals of thin filaments including composition
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
troponin subunits (3)
I, C, T
inhibitory: inhibit myosin-actin interaction
calcium: when calcium binds it removes the inhibition
tether: theres C+ I to tropomyosin
Sliding filament mechanism
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
Excitation-contraction coupling
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
How are actin and myosin regulated by free Ca2+?
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
Where do T-tubules attach and what happens?
attaches to sarcoplasmic reticulum (SR) and then it releases Ca2+ from Ca2+ release channels (ryanodine receptors)
Titin
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
costameres
type of intermediate filament that attach myofibrils to cell membrane at Z disc… have integrin
what do intermediate filaments do in relation to muscle
3D network connecting all components of muscle cell together
maintains structural integrity….
5 types of muscular dystrophy
Emery-Dreifuss MD
Myotonic MD
Duchenne’s(DMD) / Beckers (BMD) (Dystrophinopathies)
Fascioscapulohumeral MD (FSH)
Limb girdle MD (LGMD)
key characteristics of emery-dreifuss MD
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
mutations in emery dreifuss
nuclear envelope:
Emerin: X linked
Lamin A: autosomal dominant
part of LINC complex connecting nuclear lamina to cytoskeleton
most common form of muscular dystrophy in adults
myotonic dystrophy
key characteristics of myotonic dystrophy
genetic anticipation
variable symptoms and age of onset
autosomal dominant
affects multiple symptoms / organs
genetic effect in myotonic dystrophy
repeat expansion of 3/4 nucleotide repeats
expansion of a trinucleotide repeat CTG or CCTG
genetic anticipation
with each generation, there is an increase in disease severity and decrease in age of onset
(CTGs increase with each generation)
Why does repeat expansion of nucleotide repeats cause MD?
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
Key characteristics of Dystrophinopathies
X linked recessive
33% LACK family history, 66% inherited
mutations in DYSTROPHIN gene causes duchennes and beckers
Duchennes MD
DMD
severe
intellectual disabilities
lot of stuff from birth, wheelchair by 12, death by 25
OUT OF FRAME DELETIONS–> premature stop codons
Beckers MD
BMD mild symptoms later may walk until later in life NO intellectual disabilities
IN FRAME DELETIONS–> smaller but functional dystrophin
Dystrophin
largest human gene with lots of isoforms
has 4 regions
located just under muscle cell membrane
NOT FOUND in DUCHENNES MD
Dystrophin can be in complex with other proteins know as….
DAPC
creates structural and mechanical support and signal transduction
What does electromicrograph look like for skeletal muscle of DMD pt?
has center nuclei which is a hallmark of regeneration
Fascioscapulohumeral MD (FSH) charachteristics
third most common autosomal dominant genetic anticipation initially present w weakness of face and shoulders only 20% in wheelchair
mutations for FSH
heterozygous deletion in chromosome near telomere
type 2 shows heterozygous mutuation in thing required for DNA methylation
Characteristics of Limb Girdle MD (LGMD)
dominant= type 1 recessive= type 2
often diagnosed after others are excluded
> 16 gene mutations encoding muscle proteins
In MD the number of (a) cells decreases which shows the (b) capacity is limited
a) satellite
b) regenerative
intercalated discs
are specialized junctions within the cardiac muscle
*They serve as a terminal “Z” line for cells
Endomysium
connective tissue that covers each single muscle fiber AKA muscle cell