Muscle
261
(2) ATP
binding
(not hydrolysis) to myosin breaks the link
formed between actin and myosin during the cycle, allowing
the cycle to repeat.
The importance of ATP in dissociating actin and myo-
sin during step 3 of a cross-bridge cycle is illustrated by
rigor
mortis,
the gradual stiffening of skeletal muscles that begins
several hours after death and reaches a maximum after about
12 hours. The ATP concentration in cells, including muscle
cells, declines after death because the nutrients and oxygen
the metabolic pathways require to form ATP are no longer
supplied by the circulation. In the absence of ATP, the break-
age of the link between actin and myosin does not occur (see
Figure 9–8). The thick and thin fi laments remain bound to
each other by immobilized cross-bridges, producing a rigid
condition in which the thick and thin fi laments cannot be
pulled past each other. The stiffness of rigor mortis disap-
pears about 48 to 60 hours after death as the muscle tissue
decomposes.
Roles of Troponin, Tropomyosin, and Calcium
in Contraction
How does the presence of calcium in the cytoplasm regulate the
cross-bridge cycle? The answer requires a closer look at the thin
fi lament proteins, troponin and tropomyosin (
Figure 9–9
).
Tropomyosin is a rod-shaped molecule composed of two
intertwined polypeptides with a length approximately equal to
that of seven actin molecules. Chains of tropomyosin molecules
are arranged end to end along the actin thin fi lament. These
tropomyosin molecules partially cover the myosin-binding site
on each actin molecule, thereby preventing the cross-bridges
from making contact with actin. Each tropomyosin molecule
is held in this blocking position by the smaller globular pro-
tein, troponin. Troponin, which interacts with both actin
and tropomyosin, is composed of three subunits designated
by the letters I (inhibitory), T (tropomyosin-binding) and C
(calcium-binding). One molecule of troponin binds to each
molecule of tropomyosin and regulates the access to myo-
sin-binding sites on the seven actin molecules in contact with
tropomyosin. This is the status of a resting muscle fi ber; tro-
ponin and tropomyosin cooperatively block the interaction of
cross-bridges with the thin fi lament.
What enables cross-bridges to bind to actin and begin
cycling? For this to occur, tropomyosin molecules must move
away from their blocking positions on actin. This happens
when calcium binds to specifi c binding sites on the calcium-
binding subunit of troponin. The binding of calcium produces
a change in the shape of troponin, which relaxes its inhibitory
grip and allows tropomyosin to move away from the myosin-
binding site on each actin molecule. Conversely, the removal
of calcium from troponin reverses the process, turning off
contractile activity.
Thus, cytosolic calcium-ion concentration determines the
number of troponin sites occupied by calcium, which in turn
determines the number of actin sites available for cross-bridge
binding. Electrical events in the muscle plasma membrane,
which we will now discuss, control changes in cytosolic cal-
cium concentration.
Excitation-Contraction Coupling
Excitation-contraction coupling
refers to the sequence of
events by which an action potential in the plasma membrane of
a muscle fi ber leads to the cross-bridge activity just described.
The skeletal muscle plasma membrane is an excitable mem-
brane capable of generating and propagating action poten-
tials by mechanisms similar to those described for nerve cells
(Chapter 6). An action potential in a skeletal muscle fi ber lasts
1 to 2 ms and is completed before any signs of mechanical activ-
ity begin (
Figure 9–10
). Once begun, the mechanical activity
following an action potential may last 100 ms or more. The
electrical activity in the plasma membrane does not directly
act upon the contractile proteins, but instead produces a state
of increased cytosolic calcium concentration, which continues
to activate the contractile apparatus long after the electrical
activity in the membrane has ceased.
In a resting muscle fi ber, the concentration of free, ion-
ized calcium in the cytosol surrounding the thick and thin fi l-
aments is very low, only about 10
–7
mol/L. At this low calcium
concentration, very few of the calcium-binding sites on tropo-
nin are occupied, and thus cross-bridge activity is blocked by
tropomyosin. Following an action potential, there is a rapid
increase in cytosolic calcium concentration, and calcium binds
to troponin, removing the blocking effect of tropomyosin and
allowing cross-bridge cycling. The source of the increased
cytosolic calcium is the
sarcoplasmic reticulum
within the
muscle fi ber.
(a)
Low cytosolic calcium, relaxed muscle
(b)
High cytosolic calcium, activated muscle
Actin
Troponin
Tropomyosin
Energized cross-bridge
cannot bind to actin
Actin binding site
Cross-bridge binds
to actin and
generates force
Cross-bridge binding
sites are exposed
Ca
2
+
Figure 9–9
Activation of cross-bridge cycling by calcium. (a) Without calcium
ions bound, troponin holds tropomyosin over cross-bridge binding
sites on actin. (b) When calcium binds to troponin, tropomyosin is
allowed to move away from cross-bridge binding sites on actin, and
cross-bridges can bind to actin.
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