QUESTION:

Discuss the mechanisms of contraction in skeletal, smooth and cardiac muscles with
diagrams?
ANSWER: 
MECHANISM OF CONTRACTION IN SKELETAL MUSCLES
Skeletal muscle is composed of cells collectively referred to as muscle fibers. Each muscle
fiber is multinucleated with its nuclei located along the periphery of the fiber. Each muscle
fiber further subdivides into myofibrils, which are the basic units of the muscle fiber. These
myofibrils are surrounded by the muscle cell membrane (sarcolemma), which form deep
invaginations called transverse tubules (T-tubules) within the myofibril. Each myofibril
contains contractile proteins, described as thick and thin filaments, which are arranged
longitudinally into units called sarcomeres.
Skeletal muscle contraction begins first at the neuromuscular junction, which is the synapse
between a motoneuron and a muscle fiber. Propagation of action potentials to the motoneuron
and subsequent depolarization results in the opening of voltage-gated calcium (Ca2+)
channels of the presynaptic membrane. Inward Ca2+ flow causes the release of acetylcholine
(ACh) at the neuromuscular junction, which diffuses to the postsynaptic membrane at the
muscle fiber. The postsynaptic membrane of the muscle fiber is also known as the motor
endplate. ACh binds to the nicotinic receptors located at the motor endplate, depolarizing it,
which initiates the action potentials in the muscle fiber.
Excitation-contraction coupling refers to the mechanism that converts the action potentials
mentioned above in the muscle fibers into muscle fiber contraction. The action potentials at
the muscle cell membrane surrounding the myofibrils travel into the T-tubules, which are
responsible for propagating the action potential from the surface to the interior of the muscle
fiber. T-tubules contain dihydropyridine receptors that are adjacent to the terminal cisternae
of the sarcoplasmic reticulum of the muscle fiber. When T-tubules become depolarized, their
dihydropyridine receptors undergo a conformational change that mechanically interacts with
the ryanodine receptors on the sarcoplasmic reticulum. This interaction opens the ryanodine
receptors causing Ca2+ to release from the sarcoplasmic reticulum. The resulting increased
intracellular Ca2+ attaches to troponin C of the troponin complex on the thin filaments. The
interaction between Ca2+ and troponin C exhibits cooperativity, which means that each Ca2+
that binds troponin C increases the affinity of troponin C binding for the next Ca2+ molecule,
up to a total of four Ca2+ ions per troponin C. As a result of Ca2+ binding, the troponin
complex undergoes a conformational change causing displacement of tropomyosin from the
myosin-binding sites on F-actin, which allows myosin of the thick filaments to bind.
The cross-bridge cycle, an event that occurs during excitation-contraction coupling, refers to
the mechanism by which the thick and thin filaments slide past one another to generate a
muscle contraction. At the beginning of the cycle, when myosin is tightly bound to actin, no
adenosine triphosphate (ATP) is bound to myosin, a state known as rigor; this is a transient
state in contracting muscle, whereas, in the absence of ATP, such as in death, this state is
permanent and is called rigor mortis. Next, ATP binds to the myosin head, inducing a
conformational change in myosin that decreases its affinity for actin. Consequently, myosin
dissociates from actin and the myosin head becomes cocked toward the end of the sarcomere.
The ATP bound to myosin becomes hydrolyzed to adenosine diphosphate (ADP) and one
inorganic phosphate molecule, which both remain linked to myosin. In its cocked position,
myosin then binds to a new site on the actin, creating a power stroke that pulls the actin
filaments. Each cross-bridge cycling event results in the myosin head progressing up the actin
filament under the condition that Ca2+ remains bound to troponin C. Finally, ADP is
released, and myosin returns to its original state of rigor where it is bound to actin in the
absence of ATP.
After contraction, muscle relaxation occurs when Ca2+ reaccumulates in the sarcoplasmic
reticulum via the active Ca2+ ATPase (SERCA) pump on the sarcoplasmic reticulum
membrane. This pump transports the intracellular Ca2+ into the sarcoplasmic reticulum,
which maintains low intracellular Ca2+ when the muscle is relaxed. Within the sarcoplasmic
reticulum is a Ca2+ binding protein called calsequestrin, which serves to decrease free Ca2+
concentration to reduce the amount of work required by the SERCA pump. When
intracellular Ca2+ concentration decreases, Ca2+ dissociates from troponin C, allowing
tropomyosin to resume blocking the myosin-binding sites on F-actin.
The events of excitation-contraction coupling are always sequential and exhibit a temporal
relationship. In other words, the muscle fiber action potential always precedes the increase in
intracellular Ca2+, which always precedes muscle contraction. One single action potential
leading to an increased intracellular Ca2+ from sarcoplasmic reticulum release produces a
single muscle contraction known as a twitch. Because the action potential duration is shorter
than the twitch duration, the muscle fiber may be activated again before muscle relaxation
occurs. If an already active muscle fiber becomes stimulated again, there is insufficient time
for the sarcoplasmic reticulum to reaccumulate Ca2+. Consequently, intracellular Ca2+
remains high, and the force of the second stimulus becomes an additive effect to the
remainder of the first stimulus, resulting in additional force. This phenomenon of sustained
contraction is called tetany.
The force-velocity relationship refers to the velocity of muscle shortening as a function of
afterload, which is the force against which the muscle contracts. In this relationship, the
afterload is a fixed variable, in contrast to the length-tension relationship, when the muscle
length was the fixed variable. As afterload increases, shortening velocity decreases. Maximal
velocity occurs when there is zero afterload on the muscle.
Concentric contraction refers to when the force of contraction exceeds the force of resistance,
which results in muscle shortening and approximation of muscle origin and insertion.
Eccentric contraction occurs when the force of contraction is less than the force of resistance.
In other words, the force of resistance is greater than that of contraction, resulting in muscle
lengthening and an increased distance between muscle origin and insertion.

A Diagram showing skeletal muscle contraction.

MECHANISM OF CONTRACTION IN SMOOTH MUSCLE 

Smooth muscle contraction depends on calcium influx. Calcium increases within the smooth
muscle cell through two different processes. 
First, depolarization, hormones, or neurotransmitters cause calcium to enter the cell through
L-type channels located in the caveolae of the membrane. Intracellular calcium then
stimulates the release of calcium from the sarcoplasmic reticulum (SR) by way of ryanodine
receptors and IP3; this process is referred to as calcium-induced calcium release. Unlike
skeletal muscle, smooth muscle calcium release from the sarcoplasmic reticulum does not
physically couple to the ryanodine receptor. Once calcium has entered the cell, it is free to
bind calmodulin, which transforms into activated calmodulin. Calmodulin then activates the
enzyme myosin light chain kinase (MLCK), MLCK then phosphorylates a regulatory light
chain on myosin. Once phosphorylation has occurred, a conformational change takes place in
the myosin head; this increases myosin ATPase activity, which promotes interaction
between the myosin head and actin. Cross-bridge cycling then occurs, generating tension.
The tension generated is relative to the amount of calcium concentration within the cell.
ATPase activity is much lower in smooth muscle than it is in skeletal muscle. This factor
leads to a much slower cycling speed of smooth muscle. However, the more extended period
of contraction leads to a potentially greater force of contraction in smooth muscle. Smooth
muscle contraction is enhanced even further through the use of connexins. Connexins allow
for intercellular communication by allowing calcium and other molecules to flow to
neighboring smooth muscle cells. This action allows for rapid communication between cells
and a smooth contraction pattern.
Steps involved in smooth muscle cell contraction:
1. Depolarization of membrane or hormone/neurotransmitter activation
2. L-type voltage-gated calcium channels open
3. Calcium-induced calcium release from the SR
4. Increased intracellular calcium
5. Calmodulin binds calcium
6. Myosin light chain kinase activation
7. Phosphorylation of myosin light chain
8. Increase myosin ATPase activity
9. Myosin-P binds actin 
10. Cross-bridge cycling leads to muscle tone.
Dephosphorylation of myosin light chains terminates smooth muscle contraction. Unlike
skeletal muscle, smooth muscle is phosphorylated during its activation, which creates a
potential difficulty in that simply reducing calcium levels will not produce muscle
relaxation. Myosin light chain phosphatase (MLCP), instead, is responsible for
dephosphorylation of the myosin light chains, ultimately leading to smooth muscle
relaxation. 
Smooth muscle action potentials are unique in that membrane potential acts to initiate or
modulate contraction. As such, graded membrane response can become stimulated by
multiple factors, including local humoral factors, circulating hormones, or mechanical
stimulation like stretching of the cells. Action potentials in smooth muscle cells are slower
than skeletal action potentials, and they can last almost fifty times as long. This characteristic
appears to occur because calcium channels in smooth muscle cells open slower than skeletal
muscle, which, in turn, leads to slow repolarization of smooth muscle as potassium channels
are also slow to react. Sodium channels may also be present on the smooth muscle membrane
and function by increasing the rate of depolarization and thus can aid in the activation of
calcium channels. 
Smooth muscle contractions may be required to last for a long time. The metabolic demand
of sustained contraction would be far too costly if smooth muscle contractions occurred
similarly to skeletal muscle. The muscle would most likely fatigue as intracellular supplies of
ATP become depleted. The mechanism that allows the smooth muscle to maintain high-
tension at low energy consumption; termed the latch state. Even as levels of phosphorylated
myosin light chain kinase decrease, smooth muscle tone will remain high.

 A diagram showing the mechanism of smooth muscle contraction.

MECHANISM OF CONTRACTION IN CARDIAC MUSCLE 

Cardiac muscle cells (cardiomyocytes) are striated, branched, contain many mitochondria,
and are under involuntary control. Each myocyte contains a single, centrally located nucleus
and is surrounded by a cell membrane known as the sarcolemma. The sarcolemma of cardiac
muscle cells contains voltage-gated calcium channels, specialized ion channels that skeletal
muscle does not possess.
However, in cardiac contraction the cardiac action potential lasts approximately 200 ms and
is divided into 5 phases: (4) resting, (0) upstroke, (1) early repolarization, (2) plateau, and (3)
final repolarization.
Approximate resting membrane potential (RMP): -90 mV
 Phase 4 - RMP due to activity of the Na/K ATPase pump. The exchange of three
sodium ions out for two potassium ions maintains the negative intracellular potential.
 Phase 0 - depolarization to approximately +52 mv due to sodium influx via fast
sodium channels
 Phase 1 - partial repolarization due to the closure of fast sodium channels and efflux
of potassium and chloride
 Phase 2 - plateau phase maintained by the influx of calcium. Potassium efflux also
occurs.
 Phase 3 - repolarization back to RMP due to potassium efflux and closure of sodium
and calcium channels
The generation of a cardiac action potential is involuntary and proceeds via a process known
as excitation-contraction coupling (ECC). Action potentials travel along the sarcolemma and
into the t-tubules to depolarize the membrane. Voltage-sensitive dihydropyridine (DHP)
receptors on t-tubules allow calcium influx into the cell via L-type (long-lasting) calcium
channels during the plateau phase (phase 2) of the action potential. This increased
concentration of intracellular calcium triggers the sarcoplasmic reticulum to release more
calcium through the ryanodine receptor, in a process known as calcium-induced calcium-
released.
The released calcium attaches to troponin C, causing tropomyosin to detach from the myosin-
binding sites on actin. Actin and myosin then form a cross-bridge, and contraction occurs.
Cross bridges last as long as calcium is attached to troponin. Lusitropy is the term used to
define the relaxation of the myocardium following ECC. Lusitropy is mediated by
the SERCA (sarco-endoplasmic reticulum calcium-ATPase) pump, which sequesters calcium
into the sarcoplasmic reticulum, allowing calcium to be removed from troponin-C and
returning the myocardium to its relaxed state.
Unlike the cardiac muscle cells, the pacemaker cells' action potential is divided into 3 phases
instead of 5, as phases 1 and 2 are absent. Pacemaker cells are comprised of sinoatrial (SA)
and atrioventricular (AV) nodes which are known to spontaneously fire, sending electrical
activity throughout the heart, and do not require stimulation to initiate their action. This
autorhythmicity transpires because of funny current channels, which allow sodium ions to
continuously leak into the cell (Phase 4), slowly raising the membrane potential until a
certain threshold is reached, causing depolarization of the cell. This subsequently opens
calcium channels causing calcium ions to enter the cell, further raising the membrane
potential (Phase 0). After a positive membrane potential is sensed, potassium channels open,
causing an outward flow of ions, bringing the membrane potential back down to its resting
potential (Phase 3).

A diagram showing cardiac muscle contraction.