Download Muscle contraction

Metabolism of actively
contracting muscles
Fuel Utilization in Prolonged Exercise
Fuel O2 utilization
Fuel Concentrations in Blood (mM)
Blood-delivered
Fuels
Exercise
Time
(min)
Muscle
Glyc
ogen
Glucose
Fatty
Acid
0
Glucose
Lactate
Fatty
Acid
Glycerol
4.5
1.1
0.66
0.04
4.6
1.3
0.78
0.19
40
36%
27%
37%
90
22%
41%
37%
180
14%
36%
50%
3.5
1.4
1.57
0.39
240
8%
30%
62%
3.1
1.8
1.83
0.48
Data from E. A. Newsholme & A. R. Leach (1983) Biochemistry for the Medical Sciences,
John Wiley, NY. pp 370-372.
Muscle contraction
Components
involved in
Muscle
contraction
Role of Ca in Muscle contraction
The muscle cell action potential leads to release of calcium
into the cytoplasm from the sarcoplasmic reticulum (SR).
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Normally, cytoplasmic calcium level is maintained at a low level by
the activity of a calcium pump in the SR membrane.
The calcium pump uses the energy from: ATP to ADP and P, to
pump calcium into the SR. This process uses energy and creates a
concentration gradient (active transport). Thus, calcium levels in
the SR are high and there is a gradient between the cytoplasm and
the SR.
When an muscle action potential enters the proper region of the
muscle cell, it triggers the opening of calcium channels in the
membrane of the SR. Calcium will flow out of the SR into the
cytoplasm by diffusion. Contraction will be triggered.
Finally, calcium will be pumped back into the SR by the calcium
pump, this will allow relaxation to occur by removing calcium from the
cytoplasm, it will also reset the calcium gradient so that the next
contraction can be triggered.
Energy usage during muscle contraction is due both the ATP use by
myosin to energize myosin heads and also due to use of ATP by
calcium pumps to restore low levels of intracellular calcium and
enable relaxation
Interaction between Actin and
myosin in the presence of calcium.
– In the absence of calcium, interaction between myosin and
actin is prevented by the presence of tropomyosin, which
covers the myosin binding sites on actin.
– When calcium levels rise, calcium binds to troponin. The
binding of calcium changes the shape (conformation) of
troponin. In turn, troponin interacts with tropomyosin and
changes its conformation such that it no longer prevents
actin-myosin interaction.
– Contraction can occur until calcium is removed from
troponin.
Structural correlates of muscle
function
– Muscles that contract and relax quickly (i.e. a those of a
sprinter) need large amounts of sarcoplasmic reticulum with
many calcium pumps and channels.
– Muscles that are very strong (i.e. those of a weight-lifter)
need large amounts of myosin and actin.
– Muscles that are very fatigue resistant (i.e. those of a
marathon runner) need large amounts of mitochondria to
supply ATP.
– There are overlaps between these classes of muscle.
Sprinters also need to produce high levels of force and thus
also probably have high levels of actin and myosin.
– However, tradeoffs are needed because there is only a
limited amount of space in a muscle, and the relative
amounts of each component are important.
Sliding-filament model of Muscle
contraction
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An action potential originating in the CNS, reaches the axon
of the motor neuron.
The action potential activates voltage gated calcium ion
channels on the axon, and calcium rushes in.
The calcium causes the neurotransmitter, acetylcholine,
within vesicles in the axon to fuse with the plasma
membrane, releasing the acetylcholine into the synapse
between the axon and the motor end plate specialization in
the sarcolemma of the muscle.
The acetylcholine diffuses across the synapse and binds to
nicotinic receptors on the motor end plate, opening channels
in the membrane for sodium and potassium. Sodium rushes
in, while potassium trickles out through the sodium-potassium
(Na/K) pump located in the sarcolemma
However, because sodium is more permeable, the muscle
fiber membrane becomes more positively charged, triggering
an action potential.
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The action potential spreads through the muscle fibre's
network of T tubules, depolarizing the inner portion of the
muscle fibre.
The depolarization activates voltage-gated calcium
channels in the T tubule membrane, which are in close
proximity to calcium-release channels in the adjacent SR.
* Activated voltage-gated calcium channels physically
interact with calcium-release channels to activate them,
causing the SR to release calcium.
* The calcium binds to the troponin C present on the thin
filaments of the myofibrils. The troponin then allosterically
modulates the tropomyosin.
Normally the tropomyosin sterically obstructs binding sites
for myosin on the thin filament; once calcium binds to the
troponin C and causes an allosteric change in the troponin
protein troponin T allows tropomyosin to move, unblocking
the binding sites.
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Myosin (which has ADP and inorganic phosphate bound to its
nucleotide binding pocket and is in a ready state) binds to the
newly uncovered binding sites on the thin filament.
Myosin is now bound to actin in the strong binding state
(Actino-myosin). The release of ADP and inorganic
phosphate causes the myosin head to turn, causing a ratchet
movement (Actin acts as a cofactor in the release of inorganic
phosphate, expediting the release). This will pull the Z-bands
towards each other. It also shortens the sarcomere and the Iband.
ATP binds myosin, allowing it to release actin and be in the
weak binding state. (A lack of ATP makes this step
impossible, resulting in rigor mortis.) The myosin then
hydrolyzes the ATP and uses the energy to move into the
"cocked back" state while releasing ADP and inorganic
phosphate. Evidence indicates that each skeletal muscle
myosin head moves 10-12 nm each power stroke, however
there is also evidence (in vitro) of variations (smaller and
larger) that appear specific to the myosin isoform.
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Steps * are repeat as long as ATP is available
and calcium is present on thin filament.
While the above steps are occurring, calcium is
actively pumped back into the sarcoplasmic
reticulum.
When calcium is no longer present on the thin
filament, the tropomyosin changes conformation
back to its previous state so as to block the
binding sites again.
The myosin ceases binding to the thin filament,
and the contractions cease.
• The calcium ions leave the troponin molecule
in order to maintain the calcium ion
concentration in the sarcoplasm.
• The active pumping of calcium ions into the
sarcoplasmic reticulum creates a deficiency in
the fluid around the myofibrils.
• This causes the removal of calcium ions from
the troponin.
• Thus the tropomyosin-troponin complex again
covers the binding sites on the actin fiaments
and contraction ceases.
Smooth muscle contraction
• The interaction of sliding actin and myosin filaments is similar in
smooth muscle. There are differences in the proteins involved
in contraction in vertebrate smooth muscle compared to cardiac
and skeletal muscle. Smooth muscle does not contain troponin,
but does contain tropomyosin and other notable proteinscaldesmon and calponin. Contractions in vertebrate smooth
muscle are initiated by agents that increase intracellular
calcium. This is a process of depolarizing the sarcolemma and
extracellular calcium entering through L type calcium channels,
and intracellular calcium release predominately from the SR.
• Calcium release from the SR is from Ryanodine receptor
channels (calcium sparks) by a redox process and Inositol
triphosphate receptor channels by the second messenger
inositol triphosphate. The intracellular calcium binds with
calmodulin which then binds and activates myosin-light chain
kinase. The calcium-calmodulin-myosin light chain kinase
complex phosphorylates the 20 kilodalton (kd) myosin light
chains on amino acid residue-serine 19 to initiate contraction
and activate the myosin ATPase. The phosphorylation of
caldesmon and calponin by various kinases is believed to play
a role in smooth muscle contraction.
Space-filling model of the head
of muscle myosin. The model is
oriented so that the actinbinding surface is located at
the lower right-hand corner.
Three domains of the myosin
heavy chain are colored green,
red, and blue, respectively,
whereas the two light chains
are shown in yellow and purple.
ATTACHED - At the start of the
cycle a myosin head lacking a
bound nucleotide is locked
tightly onto an actin filament in
a rigor configuration (so named
because it is responsible for
rigor mortis, the rigidity of
death).
In an actively contracting
muscle this state is very shortlived, being rapidly terminated
by the binding of a molecule of
ATP.
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RELEASED - A molecule of
ATP binds to the large cleft on
the "back" of the head and
immediately causes a slight
change in the conformation of
the domains that make up the
actin-binding site. This
reduces the affinity of the
head for actin and allows it to
move along the filament.
COCKED - The cleft closes
around the ATP molecule,
triggering a large shape
change that causes the head
to be displaced along the
filament by a distance of
about 5 nm.
Hydrolysis of ATP occurs,
but the ADP and Pi produced
remain tightly bound to the
protein.
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FORCE-GENERATING - The
weak binding of the myosin
head to the new site on the
actin filament causes release
of the inorganic phosphate
produced by ATP hydrolysis,
concomitantly with the tight
binding of the head to actin.
This release triggers the
power stroke - the forcegenerating change in shape
during which the head regains
its original conformation. In the
course of the power stroke, the
head loses its bound ADP,
thereby returning to the start of
a new cycle.
ATTACHED - At the end of the
cycle, the myosin head is
again locked to the actin
filament in a rigor
configuration. Note that the
head has moved to a new
position on the actin filament.
Action wave
Calcium wave