Muscle

Sunday, July 17, 2016

2:43 PM

Important terms for Muscle

Myofibril: organized sarcomeres =filaments (actin + myosin II) within
Muscle fiber: collection of muscle cells
Sarcolemma: plasma membrane of muscle cells
T-tubule (transverse tubule): deep invagination of the sarcolemma; allows
penetration of depolarization throughout muscle quickly. (in cardiac and skeletal
muscle)
Titin: hydrophobic protein that recoils after being stretched from sarcomeric
movement. Extension of titin sequesters proteins important for inhibiting
myofibril protein production. Thus, active myofibril movement allows for the
increase in myofibril protein production.
Satellite cells in muscle: serve as a stem cell reserve that can proliferate and
fuse to form a limited number of new fibers.
myostatin which suppresses satellite cell proliferation
Triad: relationship between T-tubules and sER (sER surrounds both sides of the
T-tubule throughout the muscle fiber)
Diad: relationship between sER and t-tubules (sporatic connections between ttubules and sER)
Neuromuscular junctions (NMJ)
calmodulin : binds Ca in smooth muscle; promotes muscle contraction (via
MLCK activation and caldesmon release)
caldesmon : binds calmodulin-Ca complex and releases mysoin binding site on
actin; inhibitor of myosin contraction
Myosin light chain kinase (MLCK): phosphorylates myosin light chains resulting
in ATPase activation

1. Identify three histologically distinct classifications of muscle.

1. MC: All muscle is primarily composed of myosin (thick) and actin (thin)
filaments. The arrangement of these filaments into sarcomeres results in a
striated patterning in skeletal and cardiac muscles. No striations are visible in
smooth muscle.
Muscle fiber numbers established before birth and fibers cannot replicate.
Muscle fiber size can increase in length by terminal fusion of myoblasts
and in girth by increased size and number of myofibrils per fiber or lateral
fusion with new myoblasts.
The number and size of myofibrils can be increased by increases in
expression of genes for myofibril proteins in response to exercise and
neuronal stimulation. When stretched, titin binds regulatory proteins
which would otherwise enter the nucleus and inhibit expression of genes
for sarcomeric proteins.
Satellite cells serve as a stem cell reserve that can proliferate and fuse to
form a limited number of new fibers.
2. MC: In all forms of muscle, myosin and actin filaments interact resulting in the
sliding of these filaments relative to each other. Myosin ATPase activity provides
the force for movement.
3. MC: Expression of different isotypes of contractile (myosin II and filamentous
actin) and other proteins (actin) in muscle results in varied contractile properties
(eg, slow and fast twitch skeletal muscle).
4. MC: Contractile proteins are organized by interactions with scaffold and
intermediate filament proteins. Contractile units are linked to the membrane and
extracellular matrix for force transmission.
5. CT coverings
a. Function: (1) transmission of contractile force (2) neuro-vascular conduit
(3) protect from overstreching and tearing
b. Cell types: fibroblasts (?)
c. Types:
i. Epimysium: dense CT surrounding all fascicles and is continuouls
with the muscle fascia
ii. Perimysium: septa divide the muscle into longitudinallly oriented
fascicles
iii. Endomysium: delicate CT surrounding each muscle cell composed

c. Types:
i. Epimysium: dense CT surrounding all fascicles and is continuouls
with the muscle fascia
ii. Perimysium: septa divide the muscle into longitudinallly oriented
fascicles
iii. Endomysium: delicate CT surrounding each muscle cell composed
of basal lamina and reticular fibers
6. Sarcomere Structure (Sarcomere: contractile unit.)

a. Z-line (Z-disc): alpha-actinin joins actin filaments to join two sarcomeres

together
i. Appearance:
1) (long section) dark perpendicular line to sarcomere
2) (cross section) small dots connected by thicker lines
b. A-zone: Overlap of actin filaments and myosin II
i. Appearance:
1) (long section) dark gray lines
2) (cross section): triangles with small dots in between
c. H-zone: myosin II (thick filaments)
i. Appearance:
1) (long section) distinct dark gray lines with white in between.
2) (cross section): spaced triangles
d. I-zone: actin filaments (thin filaments), titan filaments also present (much
smaller)
i. Appearance
1) (Long section): light gray lines
2) Cross section: small dots
e. M-line: myosin II connected via M proteins
i. Appearance
1) (Long section): dark gray line surrounded by white parallel
lines
2) Cross section: triangles connected via small lines
2. Compare and contrast the structures, locations, and functions of each muscle type.

2. Compare and contrast the structures, locations, and functions of each muscle type.

Skeletal muscle: large, elongated cell, 10-100 um in diameter, up to 100 cm in length

o Muscles of skeleton, visceral striated
o Many peripheral nuclei
o No cell-cell junctions
o Well developed sER
Cardiac muscle: short, narrow cell, 10-100 um in diameter, 80-100 um in length
o Heart, SVC, IVC, pulmonary veins
o Fiber: linear branched arrangement of several cardiac muscle cells
o Single central nucleus
o Intercalated discs containing: fascia adherents, macula adherens, gap junctions
Smooth muscle: short, elongated, fusiform cell, 02.-2 um in diameter, 20-200 um in
length
o Vessels, organs, viscera
o Single smooth muscle cell
o Single central nucleus
o Gap junctions
Muscle Features Proteins
Type
Skeletal Striated
Muscle
(due to
arrange
ment of
myosin
and
actin
filamen
ts into
sarcom
eres)
MC:
Formed
by

Function Mechanis Regulatio Distribut

m
n
ion

Myosin II (thick
Moves MC: (1) Titin: Associa
filaments)
all
Contrac hydrop
ted
bones
tion is
hobic
Filamentous Actin
with
within
initiate
coil that bones
(thin filaments)
body
d by
resists Muscul
MC: Myosin
depolar stretchi
ATPase activity
otendin
ization
ng.
main force of
at the
Transcr ous
movement causing
neurom iptional junctio
the filaments to
n
uscular
factors
slide relative to
Tongue
junctio
bind
each other
n,
(inhibiti (allows
Organization
which
on of
movem
MC: The contractile
is
transcri ent in
proteins are

ts into
the filaments to
sarcom
slide relative to
eres)
each other
MC:
Organization
Formed MC: The contractile
by
proteins are
fusion
organized in to
of
parallel bundles by
myobla accessory proteins,
sts into
forming repeating
multinu structural units
cleated
termed sarcomeres
(syncyti that are continuous
al)
from one end of the
fibers,
cell to the other and
surroun insert into the
ded by
plasma membrane.
and
Desmin
attache
(intermediate
d to
filament)
connect
connect
ive
sarcomeres
tissue
and aligns in
sheaths
parallel via
which
encirculation
transmi
of Z-discs
t
Dystrophin:
contract
protein that
ile
connects actin
forces
filaments on
and
exterior of
protect
myofibril to
against
PM proteins
overstre
(complex of
tching.
proteins:
MC:
sarcoglycans,
Associa
dystroglycan
ted
), which in
satellit
turn binds an
e cells
integrin
act as
which
stem
connects with
cells for
laminin 2 (in
product
basal lamina)
ion of
allowing the
new
myofibril to
fibers.
have a
Contrac
relationship
tion of

neurom iptional junctio

n
uscular
factors
Tongue
junctio
bind
n,
(inhibiti (allows
which
on of
movem
is
transcri ent in
spread
ption)
all
to the
titin in
directio
cell
active
ns)
interior
muscle
by Tcontract Esopha
gus
tubules
ion
and
(expose (swallo
wing
then to
s
the sER hydrop
volunta
causing hobic
ry at
release
region
beginni
of
for
ng)
calcium binding Diaphra
. (2)
). Titin
Calciu
extends gm
m binds from Z- (partiall
y
troponi line to
volunta
nC,
center
ry
resultin
of
g in
sarcom
partiall
uncover ere.
y
ing of Innerva involun
the
tion of
tary)
myosin
Motor
binding neurons
site on
via
actin,
NMJ
allowin
(arise
g
from
myosin
ventral
to bind
horn of
actin in
spinal
the
cord)
presenc Tropom
e of
yosin
ATP.
regulate
(3)
d
Sliding
of actin
over
myosin
results
from a

cells for
product
ion of
new
fibers.
Contrac
tion of
each
cell is
all-ornone.
Control
of the
force of
contract
ion in a
muscle
is due
to
control
of the
number
of cells
that
contract
which
is
depend
ent
upon
the
number
of
motor
units
that
become
activate
d.
Muscle
spindle
s are
speciali
zed
muscle
cells
that
monitor
and

laminin 2 (in
basal lamina)
allowing the
myofibril to
have a
relationship
with the
endomysium
(CT).
Relatio
nship
allows
contract
ion to
be
transfer
red to
CT and
ultimat
ely the
tendon.
Alphaactinin:
microfilament
that attaches
actin
filaments to
Z-line
Triad: relationship
between T-tubules
and sER (sER
surrounds both
sides of the Ttubule throughout
the muscle fiber)
MC: The protein
titan senses
mechanical load
and controls protein
turnover and gene
expression.
Multinucleated.
Peripherally located
nuclei
Not capable of
renewal

(3)
Sliding
of actin
over
myosin
results
from a
cycle of
binding
and
release
of the
myosin
head to
the
actin
filamen
t. (4)
The
affinity
betwee
n the
myofila
ments
and the
force
generati
ng
power
stroke
(move
ment of
the
myosin
head
pullin
g the
actin
filamen
t) are
mediate
d by
ATP
and its
hydroly
sis. (5)
During
contract
ion,

speciali Peripherally located

zed
nuclei
muscle Not capable of
cells
renewal
that
monitor
and
modula
te the
extent
of
muscle
stretchi
ng.
Volunta
ry
Cardiac Striated
Muscle
(due to
arrange
ment of
myosin
and
actin
filamen
ts into
sarcom
eres)
MC:
Each
cell has
one
nucleus
and
each
fiber
consists
of
multipl
e cells
attache
d endto-end
by
adhesio
n
junctio
ns in

Myosin II (thick
filaments)
Filamentous Actin
(thin filaments)
Myosin ATPase
activity main force
of movement
causing the
filaments to slide
relative to each
other
Organization
Sarcomere
organization and
mechanisms of
contraction are
similar to that in
skeletal muscle
although protein
isotypes may differ.
Sarcomere
structure less
organized than in
skeletal muscle and
cardiac-specific
isoforms of actin,
myosin and other
sarcomeric proteins
present.
Diad: relationship

ATP
and its
hydroly
sis. (5)
During
contract
ion,
myofila
ments
slide
past
each
other
causing
the
sarcom
eres to
shorten.
MC: (1) Only
Depolar ANS
ization
innerva
is
tion(No
initiate
NMJ
d by
and do
modifie not
d
directly
cardiac
create
cells,
AP; AP
thus,
created
cardiac
from
cell
SA
contract node)
ion is Relies
indepe
on gap
ndent
junctio
of
ns
innerv Tropom
ation
yosin
by the
regulate
autono
d
mic
nervous
system.
(2)
cardiac
muscle
is kind
of a

heart,
vena
cava, and
pulmonar
y veins

d endto-end
by
adhesio
n
junctio
ns in
intercal
ated
disks.
Termin
al actin
filamen
ts insert
into the
adheren
s
junctio
ns to
transmi
t
contract
ion
from
one end
of the
cell to
the
other.
MC:
Gap
junctio
ns in
intercal
ated
facilitat
e the
spread
of
depolar
ization
from
cell to
cell
allowin
g for
coordin
ated
contract

cardiac-specific
isoforms of actin,
myosin and other
sarcomeric proteins
present.
Diad: relationship
between sER and ttubules (sporatic
connections
between t-tubules
and sER)
Intercalated discs:
sites of adhesion
and communication
between individual
muscle fibers.
Contains fascia
adherens (similar
to zonular
adherens)
Centrally located
nucleus (only one
per cell). Lots of
euchromatin (very
active nucleus).
Many organelles
located in the
center.
Fiber sizes more
uniform and often
branched
Capable of renewal

system.
(2)
cardiac
muscle
is kind
of a
differen
t thing
altoget
her there
are
really
no
nerves
in the
heart,
so to
speak.
It
generat
es its
own
action
potenti
als in
the
pacema
ker
regions
(chiefly
the SA
node)
using
speciali
zed
cardiac
myocyt
es that
self
depolar
ize (the
If
sodium
channel

cell
allowin
g for
coordin
ated
contract
ion.
MC:
Very
limited
capacit
y for
repair
by stem
cells in
the
muscle.
Involun
tary

self
depolar
ize (the
If
sodium
channel
s) fibers
in the
Purkinj
e
system/
bundle
of His
act
somew
hat like
neuron
s, but
are
actually
still
cardiac
tissue.
The
"norma
l"
cardiac
myocyt
es
themse
lves
also
conduc
t, and
propag
ate
action
potenti
als to
their
neighb
ors
through

potenti
als to
their
neighb
ors
through
gap
junctio
ns. The
only
neuron
al
innerva
tion to
the
heart is
through
the
autono
mic
nervous
system,
which
as
describ
ed
before,
can
modula
te the
functio
n of the
cardiac
myocyt
es, but
do not
interfac
e
through
a NMJ,
nor do
they
directly
create
an

a NMJ,
nor do
they
directly
create
an
action
potenti
al.
Smooth MC:
muscle
One
fiber is
one
cell.
The
cells
adhere
at
multipl
e sites
along
their
surface
s
forming
sheets
surroun
ded by
basal
laminae
and
reticula
r fibers.
MC:
Smooth
muscle
cells
are
capable
of cell
division
and
have
excelle
nt
repair
capacit

Lack sarcomeres
Myosin II (thick
filaments)
Filamenous Actin
(thin filaments)
Dense bodies:
anchored actin
filaments in the
cytosol (equivalent
of Z-discs); rich in
alpha-actinin; also
attach to
intermediate
filaments (desmin)
Myosin ATPase
activity main force
of movement
causing the
filaments to slide
relative to each
other
Spindle shaped cells
Organization
MC: Contractile
proteins align into
bundles, but the
bundles are not
organized in
parallel, but form
networks connected
to dense bodies
(alpha-actinin) in
the cell interior and
at the plasma
membrane.
Organization
of actin and

MC: (1) Neuro vessel

Contrac muscul walls,
tion is
ar
walls of
initiate
junctio digestive
d by
ns
tract, gall
nervous
absent, bladder,
or
bile duct,
hormon so
neurotr urinary
al
stimulat ansmitt tract,
er must respirator
ion of
some of diffuse y tract,
the
from
uterus,
cells
axon
eye and
which
terminu other
are
s to
organs.
electric
muscle
allycoupled cell, but
not all
by gap
cells
junctio
stimula
ns to
neighbo ted.
ring
Cell-cell
cells,
commu
allowin
nicatio
g for
n via
the
gap
coordin
ation of junctio
contract ns
critical
ion. (2)
Contrac for
tion
coordin
requires ate
a rise in contrac
cellular tion
calcium
Tropom

division
and
have
excelle
nt
repair
capacit
y.
Involun
tary

(alpha-actinin) in
the cell interior and
at the plasma
membrane.
Organization
of actin and
myosin into
web-like
networks
between
dense bodies
in cytoplasm
and dense
bodies on
plasma
membrane.
Does not
have
sarcomeres
Lacks T-tubule
system, Ca enters
cell from
extracellular milieu
via Ca channels in
extensive foldings
of membrane.
Capable of
proliferation and
hypertrophic
growth

ion. (2)
Contrac for
tion
coordin
requires ate
a rise in contrac
cellular tion
calcium
Tropom
from
yosin
both
regulate
external
d
sources
through
calcium
channel
s in
calveol
ae and
from
the
sER.
(3)
Calciu
m
stimulat
es
phosph
orylatio
n and
activati
on of
myosin
ATPase
activity.

In
smooth
muscle,
myosin is
inactive
and is
converte
d to an
active
form
when the
smooth
muscle
cell is
stimulate
d.
Stimulati

smooth
muscle
cell is
stimulate
d.
Stimulati
on of
smooth
muscle
cells
generate
s an
increase
in
cytosolic
calcium,
but
instead
of
causing
tropomy
osin to
shift as
in
skeletal
and
cardiac
muscle,
calcium
leads to
the
activatio
n of a
kinase
called
myosin
light
chain
kinase.
Calmodul
in
binds
calcium
and then
converts
MLCK
into an
active
form.
MLCK
phospho
rylates

MLCK
into an
active
form.
MLCK
phospho
rylates
myosin
light
chains
which
associate
with
muscle
myosin.
When
the light
chains
are
phospho
rylated,
the
myosin is
active
and able
to
generate
contracti
on.

Neural
or
hormon
al
stimula
tion
causes
Ca
influx
through
Ca
channel
s in
smooth
muscle
cell
plasma
membr
ane..

smooth
muscle
cell
plasma
membr
ane..
Ca
binds
to
calmod
ulin
and CaCalmod
ulin
binds
to and
activate
s
myosin
light
chain
kinase
resultin
g in
phosph
orylatio
n of
myosin
light
chains
and
ATPase
activati
on.
CaCalmod
ulin
also
binds
caldes
mon
resultin
g in its
phosph

binds
caldes
mon
resultin
g in its
phosph
orylatio
n and
displac
ement
from
actin
where
it can
block
myosin
binding
.
Myosin
sliding
of actin
is
transmi
tted to
actinin
attach
ment
points
in
cytosol
and at
plasma
membr
ane
resultin
g in 3D
cell
contrac
tion.
Contrac
tion is
relaxed
by

tion.
Contrac
tion is
relaxed
by
dephos
phoryla
tion of
myosin.

3. Define the molecular basis of contraction in each muscle type.

1. Skeletal Muscle:
a. Innervation: NMJ
b. Regulation: Tropomyosin and troponin complex mediated
c. Source of Ca2+: mainly intracellularly (sER sequestered)
2. Cardiac Muscle:
a. Innervation: only ANS (no NMJ)
b. Regulation: Tropomyosin and troponin complex mediated
c. Source of Ca2+: some intracellular and some extracellular
3. Smooth Muscle:
a. Innervation: diffusion of NT (no NMJ); mainly relies on gap junctions
b. Regulation: Tropomyosin and troponin complex mediated
c. Source of Ca2+: mainly extracellular Ca2+
4. Speed of contraction:
a. Fast twitch:
Type 2 (fast twitch, White) fibers: less myoglobin, high glycogen, fewer
mitochondria, rapid contraction, low endurance, anaerobic, high number
of neuromuscular junctions for fine control.
b. Intermediate twitch:
Type 2a, 2b, and 2c intermediate forms of fibers with varying
characteristics
c. Slow twitch:
Type 1 (slow twitch, Red) fibers: rich in myoglobin, low glycogen, many
mitochondria, slow contraction. Used when sustained force is required as
in postural muscles and limbs
4. Demonstrate the mechanisms which control contraction.
1. Regulatory Proteins:
a. Tropomyosin: coiled coil protein
b. Troponin Complex
i. Troponin C: binds Ca2+ forming the troponin complex
ii. Troponin I: binds actin to hold the actin:tropomyosin complex
together
iii. Troponin T: binds to tropomysoin

i. Troponin C: binds Ca2+ forming the troponin complex

ii. Troponin I: binds actin to hold the actin:tropomyosin complex
together
iii. Troponin T: binds to tropomysoin

2. Skeletal Motor Innervation:

One nerve axon usually splits into several nerve terminals.

The axon of motor neurons will often branch to allow a single motor neuron to
synapse with multiple skeletal muscle cells. However, each muscle cells is
innervated by only one neuron.

Each terminal will innervate a separate muscle fiber.

The action potential in one motor neuron sets off a response in several
cells.
Motor unit nerve plus all the muscle cells it innervates.
All fibers within a motor unit are of they same type (ie type I, II or
intermediate).
Motor units vary considerably in size
Eye one nerve to approximately 3 muscle fibers
Postural muscles one nerve to hundreds of fibers
Mechanism
a. Presynaptic membrane is depolarized causing Ca channels to open and Ca
to enter axon terminus.
b. Ach vesicles fuse with presynaptic membrane releasing Ach into synaptic
cleft.
c. Ach binds to and opens Na channels on postsynaptic membrane causing

a. Presynaptic membrane is depolarized causing Ca channels to open and Ca

to enter axon terminus.
b. Ach vesicles fuse with presynaptic membrane releasing Ach into synaptic
cleft.
c. Ach binds to and opens Na channels on postsynaptic membrane causing
muscle membrane depolarization which spreads to T-tubule. Ach is
rapidly degraded by Achase.
d. Voltage sensors in T-tubule change conformation and, in turn, alter
conformation of Ca channels in sER resulting in release of Ca to muscle
cytosol.
e. Ca binds troponin C initiating changes in troponin I which uncover myosin
binding sites on actin.
f. Ca is pumped back into sER by Ca ATPase, and contraction stops (30
msec).

Resting potential
Out: High Na+ and Low K+ (maintained by Na+/K+ ATP pump --> 3 Na+/2K+)
In: Low Na+ and High K+

 Ach binding to AchR

Opens Na+ channel.

How can you tell the histological differences between a sensory and motor nerve
(specifically cross-section)?
5. Compare mechanisms of muscle growth and repair.
1. Muscle fibers secrete myostatin which suppresses satellite cell proliferation
and maintains a balance in muscle mass. Reduction in myostatin production
due to muscle damage and wasting activates satellite cell proliferation and

(specifically cross-section)?
5. Compare mechanisms of muscle growth and repair.
1. Muscle fibers secrete myostatin which suppresses satellite cell proliferation
and maintains a balance in muscle mass. Reduction in myostatin production
due to muscle damage and wasting activates satellite cell proliferation and
fusion leading to repair. Mutations causing reduced myostatin lead to
individuals with increased muscle mass due to increased fiber numbers and
size. -> Mouse myostatin KO = muscle mouse
6. Describe the histological changes in myopathies such as Duchennes muscular
dystrophy or denervation atrophy.
Muscular Dystrophy : Diverse mutations result in aberrant links between
sarcomere and connective tissue (eg, mutations in dystrophin, sarcoglycans,
dystroglycans, laminin 2). Results in stress-induced fiber degeneration.