e Fisiologa y B

ad io

n
CONTRACCIN

log
Sociedad Per ua

a M
MUSCULAR

olecular
Prof: Pedro Nez

Lima 2013
CONTRACCIN MUSCULAR visin general
Anatoma
Msculo esqueltico
Msculo estriado
 Myofiber anatomy

Sarcoplasmic reticulum
lies next to T tubules.

Transverse tubules=
infoldings of sarcolemma.
Myofiber anatomy
Motor Unit
Muscles
Spindle apparatus
 Sarcoplasmic Reticulum (SR)
SR - an elaborate, smooth ER that surrounds each
myofibril. Perpendicular (transverse) channels at the
A band - I band junction are the Terminal Cisternae.
SR regulates intracellular Ca2+

Terminal Cisterna
 T Tubules (transverse)
T tubules at each A band - I band junction are
continuous with the sarcolemma. The lumen of the
tubule is continuous with the extracellular space.
Conduct electrical impulses to the muscle (every
sarcomere) - signals for
the release of Ca2+ from
adjacent terminal cisternae

T tubule
Triad 2 terminal cisternea and 1 T tubule
Relationship of SR and T
tubules to myofibrils
Msculo esqueltico
SARCOMERE
 S1
Light chains
Myosin 160 nm
ELC

Heavy chains
-helical coiled-coil RLC

S1 - Molecular Motor of Muscle Contraction

Alpha-actinin
 28,000 amino acids (3MDa)
Titin the largest protein known in
mammals.

Z Z
Titin is located in the space between the two filaments, attached at various points to the
myosin, and it runs all the way to the Z-disc at either end of the sarcomere. The protein is
thought to act as a sort of spring mechanism that keeps the myosin filament centered in the
sheath as the whole structure expands and contracts.
Msculo esqueltico
Sliding Filament Theory of
Contraction
Msculo esqueltico ( protenas: miosina 460,000. actina 43,000 TM: 70, T: 18)
 Myosin II
heavy
chain
motor
-helical domains
coiled coil light
chains

Myosin II was first studied for its role in muscle contraction, but it functions
also in non-muscle cells.
Myosin II includes 2 heavy chains.
The globular motor domain of each heavy chain catalyzes ATP
hydrolysis, and interacts with actin.
Each heavy chain continues into a tail domain in which heptad repeat
sequences promote dimerization by interacting to form a rod-like -
helical coiled coil.
La miosina pertenece a una superfamilia de protenas formado por 20
tipos
18.4 A rise in cytosolic Ca2+ triggers
muscle contraction

Figure 18-31
 18.4 Tropomyosin and troponin regulate
contraction in skeletal muscle
Tropomyosin

Figure 18-32

Binding of Ca+2 to TN affects the positioning of TM on actin filaments

Thin Filament Regulatory Proteins:
From Gordon et al., 2000

Tropomyosin consists of two -helical chains (each 35kD) that form a coiled-coil about 40 nm
long which snakes down the middle of the actin helices. It is polymerized end to end along each
of the two grooves of the F-actin filament providing structural stability and modulating the
filament function. Troponin is composed of three subunits which interact strongly with one
another: the Ca2+-binding troponin C (TnC), the inhibitory troponin I (TnI) and the Tm-binding
troponin T (TnT) subunits. The TnT-Tm interaction, which is specific to striated muscles, is
essential for Tn binding to the thin filament with proper stoichiometry of 1 Tn : 1 Tm : 7 actin.
 Excitation-Contraction Coupling
Some of the Ca2+ binds to troponin, troponin changes
shape and causes tropomysin to move which exposes
the active binding sites on actin
Myosin heads can now alternately attach and detach,
pulling the actin filaments toward the center of the
sarcomere (ATP hydrolysis is necessary)
 Excitation-Contraction Coupling
The short calcium influx ends (30 ms after the action potential ends) and Ca2+
levels fall. An ATP-dependent Ca2+ pump is continually moving Ca2+ back
into the SR.
Tropomyosin blackage of the actin binding sites is reestablished as Ca2+ levels
drop. Cross bridge activity ends and relaxation occurs
 Thin Filament Regulatory Proteins
Two Tropomyosin strands spiral around the actin filament and block the
active sites in a relaxed muscle fiber

Troponin is a three-polypeptide complex:

TnI - Inhibitory subunit that bunds to actin
TnT - binds to Tropomyosin
TnC - binds Calcium ions
 Ca2+ and the Contraction Mechanism

At low intracellular Ca2+, tropomyosin blocks the

binding sites on actin and myosin cannot attach
this is the relaxed state.
 Ca2+ and the Contraction Mechanism

As Ca2+ levels rise, ions bind

to troponin regulatory sites
Calcium-activated
troponin binds an
additional two Ca2+ at a
separate regulatory site
(inactive troponin binds
two Ca2+)
 Ca2+ and the Contraction
Mechanism
Calcium-activated troponin
undergoes a conformational
change
This change moves
tropomyosin away from
actins binding sites
 Ca2+ and the Contraction
Mechanism
Displacement of the
tropomysosin allows the
myosin head to bind and
cycle (attach and detach)
Contraction begins (sliding of
the thin filaments due to
action of the myosin cross
bridges)
 Sequential Events of Contraction
Cross bridge formation myosin cross bridge
attaches to actin filament

Working (power) stroke myosin head pivots and

bends, pulling actin
filament toward M line
 Sequential Events of Contraction

Cross bridge detachment ATP attaches to

myosin head and the
cross bridge detaches

Cocking of the myosin head energy from

hydrolysis of ATP cocks the
myosin head into the
high-energy state
Sequential Events of Contraction
ATPase Cycle:

1. A M + ATP

2. A+ MATP

3. A M ADP Pi
Pi release rate:
Pi
10-20s-1
4. A M ADP +Pi

ADP

5. A M +ADP
Anatoma de la fibra muscular esqueltica y cardica
Fibra muscular esqueltica y cardiaca
Miocito
Fibra muscular cardiaca
Contraccin muscular cardiaca
Contraccin muscular esqueltica
TITIN (TTN). Viene de la mitologa griega del gigante titan, - Es una protena
sarcomrica mas grande, el corazn expresa dos isoformas de TTN, (N2B y
N2BA), que incorpora 4 regiones distintas: Linea Z, banda I, banda A y lnea
M; juega un rol central en la estructura, mecnica y regulatorio del sarcmero
del msculo estriado. El gen del TTN tiene 364 exones y localizado en el gen
2q31, con 4200 kDa, formado de 38.000 residuos de AA, mantiene la
arquitectura y organizacin durante las contraccin y desarrolla tensin pasiva
durante la relajacin
La banda I es responsable de la rigidez del msculo cardiaco y por lo tanto de
la cardiomiopatas en particular la cardiomiopata dilatada(DCM),
caracterizado por disfuncin sistlica con dilatacin del VI o biventricular y
causar la cardiomiopata arritmigena del VD(ARVC), mientras las
cardiomiopatas restrictivas e hipertrficas tiene fondo gentico.
Other Thick Filament Proteins:
Myosin binding protein C MW 140 kDa
binds to myosin tail region
X- protein- MW 134 kDa
H- protein- MW 55 kDa
M-line proteins: creatine kinase (40kDa), M-protein (165 kDa),
myomesin (185 kDa).
M-line
Thin Filament Proteins:
Z-line

F-actin

Z-line
Myosin binding protein C (MyBP-C): Es una protena, filamento delgado, unido
ajustadamente a la meromiosina ligera,(LMM) miosina S2, su finalidad es para
limitar la propiedad contrctil de los miofilamentos,
Regulation
Regulation
Mecanismo de la contraccin ( actina y miosina para formar actomiosina)
Myosin cycle
 F-actin is composed of a double
helical strand of thousands of
polymerized G actin (43kd)
molecules.

480 kd subunits
480 kd subunits

Myosin is a Double Trimer

About 200 myosin molecules

form a single thick filament. The
helix is in the filament and the
heads stick out sideways on
both ends with 120 degree
spacing.
 Tropomyosin (70 kd, about
400 long) is an accessory
protein that inhibits cross bridge
formation by its interaction with
troponin
480 kd subunits
480 kd subunits
Troponin (50 kd) is a second accessory
protein that controls the tropomyosin
conformation. It is a trimer with 3
subunits.

1. C subunit binds Ca++

2. I subunit directly covers the
myosin-binding site on actin and
inhibits cross bridge formation.
3. T subunit binds tropomyosin.
When activated with Ca++ the
tropomyosin moves away from the
actin strand pulling the troponin I
away to allow cross bridge formation.
In all striated muscle Ca++ binds
to troponin C.
1. Tropomyosin undergoes
conformational change, so that
actins myosin binding sites are
exposed.
2. The cross bridge cycle repeats
as long as calcium is present.

Troponin C = Calcium binding

Troponin I = Inhibits X-bridges
Troponin T = modulates
Tropomyocin
The action potential is carried to the interior of the cell by the
transverse tubules. That allows rapid activation of the interior of
these big (25u) cells.
In cardiac muscle Ca++ coming out of the transverse tubules (trigger
calcium) binds to ryanodine receptors and cause Ca++ stored in the
sarcoplasmic reticulum to be released into the cytosol.
1
Skeletal muscle only

Cardiac muscle only

2
3
Relacin tensin longitud en la contraccin muscular
Mecanismo de la contraccin y relajacin cardiaca

Figure 14-11: Excitation-contraction coupling and relaxation in cardiac muscle

Tipos de contraccin
Contraccin del msculo estriado
Contraccin de la fibra muscular lisa
 Intermediate filaments, dense bodies,
and dense bands of smooth muscle fibers
 Msculo liso:
Son estructuras fusiformes, ms pequea que las del msculo
esqueletico, pero con ncleo central y fijadas a la matriz conectiva.
Se distingue dos tipo de msculo liso:
a.- unitario visceral: propio de las vsceras huecas (intestinos,
tero, vasos sanguneos) donde se presentan en fascculos capas
de clulas yuxtapuestas. Estas clulas reciben escasa inervacin y
tienen actividad elctrica y mecnica espontnea que se propaga or
los gap junctions ( comportamiento sincitio funcional).
b.- multiunitario: esta compuesto por clulas musculares lisas
independientes, con pocas uniones intercelulares y generan
contracciones finas y localizadas. Esta clulas reciben alta
densidad de terminaciones nerviosas, donde cada uno inerva una
nica clula muscular. Esta clula encontramos en el msculo ciliar
del iris
La clula muscular lisa presenta filamentos finos de actna F y
tropomiosina y poca cantidad de miosina . Carece de troponina,la
miosina es globular y la actina filamentosa que al contraerse reduce
su longitud hasta en el 150% y consume ATP para la contraccin en
menor magnitud que el esqueltico.
La contraccin y relajacin es lenta, la contraccin dura horas
No hay tubulos en T si no caveolas , sintetizan protenas y factores
de crecimiento y pueden incrementar de volumen y nmero
Berne, R.M., Levy, M.N., Koeppen, B.M., & Stanton, B.A. Physiology: 5th Ed. 2004.
Smooth Muscle
Contraccin de la fibra muscular lisa se realiza por la entrada de Ca++
por los canales L y T y se describe en: mediado por hormonas
(acoplamiento farmacomecnico) por P A. (electromecnico)
 RLC
Regulation of Smooth Muscle Contraction:
The smooth muscles lack troponin
Phosphorylation of the myosin RLC with Ca2+-CaM
MLCK initiates contraction
Caldesmon (CaD) binds to actin filaments and prevents myosin binding
When [Ca2+] arrives its binds to CaM and the Ca2+-CaM complex binds CaD allowing
myosin heads to interact with actin.

Myosin RLC

Myosin Phosphorylated-RLC
Acoplamiento farmaco-mecnico: Ang II, catecolaminas, TxA2, contraccin lenta
actuando sobre receptor acoplado de protena Gq>> PLC hidroliza IP2 >>IP3.>>Ca
Acoplamiento electromecnico: PA>> contraccin.
In smooth muscle Ca++ binds to camodulin.
1. MLCK phosphorylates myosin light chains.
2. X-bridge cycling repeats as long as myosin light chains
are phosphorylated
3. A phosphatase finally removes the phosphate to relax
the muscle.
Contraccin de la fibra muscular lisa vascular por estmulo
farmacomecnico.
Relajacin de la fibra muscular lisa vascular
Contraccin de la fibra muscular lisa
Clula muscular lisa presenta contraccin rpida (fsica) lenta (tnica). El
PTR es de -50 -70 mV, y el PA se atribuye al Ca++. La actividad elctrica
puede ser: a.-espontnea, de ondas lentas sin respuesta contrctil y el PA
alcanza -35 produce contraccin fsica. b.- por PA (espigas) y .- PA de
repolarizacin retrasada. (tero).
Msculo liso en comparacin de otros msculos. El ANS no hace contacto
con la fml, si no que se ramifica difusamente entre ellas, secreta el NT. El ANS
no genera, si no modula la contraccin. As en el aparato digestivo la Ach
despolariza y aumenta la actividad migena espontnea y la NA lo contrario,
igual en los bronquios donde el 2 es relajador, en los vasos es al contrario.
En el tero los estrgenos despolariza y la progesterona hiperpolariza.