2. Contraction
For contraction, skeletal muscle
must:
be stimulated by a nerve ending
propagate an action potential, along its
sarcolemma
have a rise in intracellular Ca2+ levels,
the final stimulus for contraction
Ca2+ levels may rise from its resting
level of less than 10-7 M to greater than
10-5 M
3. Theories of Muscle Contraction
New elastic body theory (1840 – 1920 )
Fenn observed that total energy released by
muscle (work +heat) increases as muscle work
increases this is known as “FENN EFFECT”
Continuous filament theory –
According to this theory, during contraction
actin & myosin combine to form 1 continuous
filament which undergoes folding & shortening
Electron microscope observations do not
support this theory as after contraction length
of thick & thin filament is not altered only their
relative position changes
4. Theories of Muscle Contraction
Sliding Filament Theory (1954): Huxley
and Niedergerke
Sliding filament theory was transformed into
Cross Bridge cycle (1957): Huxley
Thin filament slides past thick filament
Molecular basis of sliding motion is by
globular head of myosin forming cross
bridges with actin monomers (Huxley’s
Cross Bridge theory) or Ratchet theory of
muscle contraction / Walk along Theory
5. Sliding Filament Theory
Thin filament slides
over the thick
Width of A band
constant
Z-lines
move closer –
contraction
move apart –
relaxation
A. Relaxed
I band
sarcomere
A band
M line
Z
disk
B. Contracted
8. Excitation –Contraction Coupling
Sequence of events linking the
transmission of an action potential along
the sarcolemma
to
muscle contraction
(the sliding of myofilaments)
9. Excitation Contraction(EC) coupling
The entire process, extending from
depolarization of the T-tubule membrane
to the initiation of cross-bridge cycling, is
termed Excitation Contraction coupling or
EC coupling
Action potential travels along T-Tubules
leading to Ca++ release from sarcoplasmic
reticulum leading to contraction
10. Excitation Contraction(EC) coupling
Electrical Event
Action potential generated in muscle fiber memb.
due to depolarization of motor end plate
AP transmitted along muscle fiber – initiates
contractile response
Mechanical Event
Contraction via contractile protein myosin and
cytoskeletal protein actin
`
Single AP causes a brief contraction followed
by relaxation – Simple Muscle Twitch
11. Electrical and Mechanical
Response
Plotted on the
same time scale
Twitch starts about 2 ms
after start of depolarization
of membrane & before
repolarization is complete
Duration of twitch varies
with type of muscle
"Fast" muscle fibers- fine, rapid,
precise movement - twitch
durations as short as 7.5 ms
"Slow" muscle fibers - strong,
gross, sustained movements -
twitch durations up to 100 ms
12. Action Potential
RMP = -90mv
AP lasts for 2-4 milliseconds (ms),
conducted along muscle fiber at 5 m/sec
with ARP = 1-3 msec
Ends before contraction occurs
Period between action potential initiation
and the beginning of contraction is called
the latent period
Excitation-contraction coupling occurs
within the latent period
16. STEPS IN CONTRACTION
Neurotransmitter acetylcholine (ACh)
binds to its receptors on the motor end
plate
Ligand gated ion channels in the receptors
open and allow Na+ and K+ to move
across the membrane
depolarization
18. T – system orTransverse TubularSystem
Contains L-type Ca2+ channels clustered in
groups of four called "tetrads“
Each is in fact a heteropentameric protein
Each of the four Ca2+ channels is also called a
DHP receptor because inhibited by class of
antihypertensive drugs known as
dihydropyridines
Function as voltage sensor in EC coupling
Depolarization of T-tubule activates
longitudinal sarcoplasmic reticulum via
DHP receptors
19. Ca2+ channel in Sarcoplasmic Reticulum
a.k.a ryanodine receptor
Because inhibited by class of drugs that include
the plant alkaloids ryanodine and caffeine
Homotetrameric structure
Each of the four subunits of these channels
has a large extension-also known as a
"foot.“
Ligand gated Ca2+ channel with calcium as
its natural ligand
Ca2+ -induced Ca2+ release (CICR)
20. Depolarization of T-tubule
Each L-type Ca2+ channel interacts with foot of
one of the 4 subunits of the Ca2+-release channel
Depolarization of T-tubule evokes conformational
changes in each of the four L-type Ca2+ channels
and has two effects
Conformational changes allow Ca2+ to enter through the
four channel pores
Second, and much more important, the conformational
Ca2+
changes in the four L-type channels induce a
conformational change in each of the four subunits of
another channel-the Ca2+-release channel-that is located
in the SR membrane
21.
22.
23.
24.
25. Ca++ binds with Troponin C
Troponin – Tropomyosin complex inhibits
the interaction between actin and myosin
When Ca++ binds to Trop C, active sites of
actin are uncovered & ATP is split to ADP
releasing P- energy & contraction occurs
Excitation Contraction(EC) coupling
26. Troponin
Each troponin C molecule in skeletal muscle has
2 high-affinity Ca2+ -binding sites
2 low-affinity Ca2+-binding sites
Binding of Ca2+ to low-affinity sites induces a
conformational change in the troponin complex
that has two effects
troponin I moves away from the actin/tropomyosin
filament, thereby permitting the tropomyosin molecule
to move
troponin T pushes tropomyosin away from the myosin-
binding site on the actin and into the actin groove
With the steric hindrance removed, the myosin
head is able to interact with actin and engage in
cross-bridge cycling
27.
28. Cross Bridge Cycle
In presence of calcium, myosin head binds to an
actin filament
Changes its orientation relative to myosin filament
which causes filaments to slide relative to each
other - Power Stroke
During the Cross-Bridge Cycle, Contractile Proteins
Convert the Energy of ATP Hydrolysis Into
Mechanical Energy
Each power stroke shortens sarcomere by 10nm
Cross bridge cycling is asynchronous
500 myosin in one thick filament, each head cycling 5
times per second
29.
30. Cross Bridge Cycle
Occurs in 5 steps :-
1. Cross – Bridge formation –
cocked myosin head (perpendicular or
at a 90-degree angle to the thick and
thin filaments) binds to actin filament
Cocked head has the stored energy
derived from the cleaved ATP
31. Cross Bridge Cycle
2. Release of Pi from the myosin
Dissociation of Pi from the myosin head
triggers power stroke
Conformational change - myosin
head bends approximately 45º about
the hinge
Pulls the actin filament about 11 nm
myosin
toward the tail of the
molecule
Generating force and motion
32. Cross Bridge Cycle
3. ADP release –
Dissociation of ADP from myosin
Myosin head remains in the same position
(45º angle with respect to the thick and
thin filaments)
4. ATP binding –
ATP binding to the head of the myosin
heavy chain (MHC) reduces the affinity of
myosin for actin
Myosin head releases actin filament
33. Cross Bridge Cycle
5. ATP hydrolysis –
Breakdown of ATP to ADP and inorganic
phosphate (Pi) occurs on myosin head
Products of hydrolysis are retained on the myosin
As a result of hydrolysis, the myosin head pivots
around the hinge into a "cocked" position
(perpendicular or at a 90º angle to the thick and
thin filaments)
Rotation causes the tip of the myosin to move
about 11 nm along the actin filament so that it
now lines up with a new actin monomer two
monomers further along the actin filament
34. Cross Bridge Cycle
Cycle repeats as long as Ca2+ is elevated
and sufficient ATP is there
Muscle cells do not regulate cross-bridge
cycling by modifying [ATP]i
Instead, skeletal muscle and cardiac
muscle control this cycle by preventing
cross-bridge formation until the
tropomyosin moves out of the way in
response to an increase in [Ca2+]i
45. Steps in Relaxation
Cell may extrude Ca2+ using either an Na-
Ca exchanger (NCX) or a Ca2+ pump(PMCA)
However, would eventually deplete the cell of
Ca2+ and is thus a minor mechanism for Ca2+
removal from the cytoplasm
Instead, Ca2+ re-uptake into the SR is the
most important mechanism by which the
cell returns [Ca2+]i to resting levels
Ca2+ re-uptake by the SR is mediated by a
SERCA(s arcoplasmic or e ndoplasmic
r eticulum C a2+A TPase )-type Ca2+ pump
46. Steps in Relaxation
SR Ca2+-pump activity is inhibited by high [Ca2+]
within the SR lumen
Inhibition of SR Ca2+-pump activity is delayed by
Ca2+-binding proteins within the SR lumen
Buffer the Ca2+ increase in the SR during Ca2+ re-uptake
and thus markedly increase the Ca2+ capacity of SR
Proteins have a tremendous capacity to bind Ca2+ with
up to 50 binding sites per protein molecule
Principal Ca2+ binding protein in skeletal muscle,
calsequestrin
also present in cardiac and some smooth muscle
Calreticulin - Ca2+-binding protein found in particularly
high concentrations within the SR of smooth muscle
47.
48. Steps in Relaxation
When Ca++ conc. outside has lowered,
interaction of actin & myosin ceases & muscle
relaxes
ATP required for both contraction &relaxation
Pump concentrates Ca++ about 10,000fold
Normal/Resting Ca++ conc. (less than 10-7
moles of Ca++ ) rises to 10-5 M
Total duration of Ca++ ions stay in fluid is
1/30th of sec
49. Contracture
Ca2+ movement inhibited
Relaxation fails to occur
Cross bridges don’t break
Sustained contraction despite no action
potential
50. Role of ATP
Provides energy
myosin head
for power stroke of
Brings about a dissociation of myosin head
from actin filament
Brings about muscle relaxation by
Ca2+
pumping back into sarcoplasmic
reticulum
51. Rigor Mortis
Muscles of body become very stiff and
rigid shortly after death
Due to loss of ATP in the muscle cell
In absence of ATP, the myosin cross
bridges with actin is not broken, so, no
relaxation occurs
15-25 hrs later, muscle proteins
deteriorate and rigor disappears
52.
53.
54.
55.
56.
57. EC Coupling: Drugs
Blocking release of Ca++ from SR
keeps muscle relaxed, even in the presence of
action potential eg Ryanodine receptor blocker
like Protamine sulphate
Caffeine cause release of Ca++
produces contraction without action potential
Drugs which increase the release of Ca++
from sarcoplasmic reticulum. eg. Digitalis
increase the force of cardiac muscle
contraction
58. Malignant Hyperthermia
Channelopathy of calcium release channel in
muscle (Ryanodine receptors)
constant leak of SR Ca2+ through ryanodine receptor
triggered by halogenated anesthetics (isoflurane, halothane)
or severe exercise
familial tendency - can be tested for by muscle biopsy
Symptoms
Normal muscle function under normal conditions
increased body temperature -more heat produced
skeletal muscle rigidity
lactic acidosis (hypermetabolism)
59. Thank you
References:
Guyton- Textbook of Medical Physiology
Ganong’s- Review of Medical Physiology
Boron-Medical Physiology
Kandel-Principles of Neural Science
Silbernagl-Color atlas of Physiology
Ira Fox- Medical Physiology
