MECHANISM OF MUCLE CONTRACTION

All skeletal muscle contractions occur as a result of conscious effort originating in the brain. The brain
sends electrochemical signals through the somatic nervous system to motor neurons that innervate
(stimulate) muscle fibers. A single motor neuron with multiple axon terminals can innervate multiple
muscle fibers, thereby causing them to contract at the same time. The connection between a motor
neuron axon terminal and a muscle fiber occurs at a neuromuscular junction site.

For the contractions to happen, the muscle cells must rely on the interaction of two types of filaments:
thin and thick filaments.

The major constituent of thin filaments is a chain formed by helical coiling of two strands of actin, and
thick filaments dominantly consist of chains of the motor-protein myosin. Together, these two filaments
form myofibrils - the basic functional organelles in the skeletal muscle system.

 (Actin, protein that is an important contributor to the contractile property of muscle and other
cells. It exists in two forms: G-actin (monomeric globular actin) and F-actin (polymeric fibrous
actin), the form involved in muscle contraction.)
 (Myosin is the prototype of a molecular motor—a protein that converts chemical energy in the
form of ATP to mechanical energy, thus generating force and movement.)

In vertebrates, skeletal muscle contractions are neurogenic as they require synaptic input from motor
neurons. A single motor neuron is able to innervate multiple muscle fibers, thereby causing the fibers to
contract at the same time. Once innervated, the protein filaments within each skeletal muscle fiber slide
past each other to produce a contraction, which is explained by the sliding filament theory. The
contraction produced can be described as a twitch, summation, or tetanus, depending on the frequency
of action potentials.

The sequence of events begins when an action potential is initiated in the cell body of a motor
neuron, and the action potential is propagated along the neuron’s axon to the neuromuscular junction.
Once the action potential reaches the end of the axon terminal, it causes the neurotransmitter
acetylcholine (ACh) from synaptic vesicles in the axon terminal. The ACh molecules diffuse across the
synaptic cleft and bind to the muscle fiber receptors, thereby initiating a muscle contraction. Muscle
contraction is initiated with the depolarization of the sarcolemma caused by the sodium ions' entrance
through the sodium channels associated with the ACh receptors.

A neuromuscular junction is a chemical synapse formed by the contact between a motor neuron and a
muscle fiber. It is the site in which a motor neuron transmits a signal to a muscle fiber to initiate
muscle contraction.
Immediately following depolarization of the membrane, it repolarizes, re-establishing the negative
membrane potential. Meanwhile, the ACh in the synaptic cleft is degraded by the enzyme
acetylcholinesterase (AChE). The ACh cannot rebind to a receptor and reopen its channel, which would
cause unwanted extended muscle excitation and contraction.

Propagation of an action potential along the sarcolemma enters the T-tubules. For the action potential
to reach the membrane of the Sarcoplasmic Reticulum (SR), there are periodic invaginations in the
sarcolemma, called T-tubules (“T” stands for “transverse”). The arrangement of a T-tubule with the
membranes of SR on either side is called a triad.

The triad surrounds the cylindrical structure called a myofibril, which contains actin and myosin. The T-
tubules carry the action potential into the interior of the cell, which triggers the opening of calcium
channels in the membrane of the adjacent SR, causing Ca2+ to diffuse out of the SR and into the
sarcoplasm. It is the arrival of Ca2+ in the sarcoplasm that initiates contraction of the muscle fiber by its
contractile units, or sarcomeres.

Excitation-contraction coupling

Excitation–contraction coupling (ECC) is the process by which a muscular action potential in the
muscle fiber causes myofibrils to contract. For a skeletal muscle fiber to contract, its membrane must
first be “excited”—in other words, it must be stimulated to fire an action potential. The muscle fiber
action potential, which sweeps along the sarcolemma as a wave, is “coupled” to the actual contraction
through the release of calcium ions (Ca++) from the SR. Once released, the Ca++ interacts with the
shielding proteins, troponin and tropomyosin complex, forcing them to move aside so that the actin-
binding sites are available for attachment by myosin heads. The myosin then pulls the actin filaments
toward the center, shortening the muscle fiber.

 (Troponin is a protein complex found in muscle cells, particularly in cardiac (heart) and skeletal
muscle. It plays a crucial role in regulating muscle contraction. The troponin complex consists
of three subunits: troponin C, troponin I, and troponin T.)
 (Tropomyosin are a large family of integral components of actin filaments that play a critical
role in regulating the function of actin filaments in both muscle and nonmuscle cells.)

Sliding Filament Theory of Muscle Contraction

The sliding filament theory describes a process used by muscles to contract. It is a cycle of
repetitive events that cause a thin filament to slide over a thick filament and generate tension in the
muscle. According to this theory, muscle contraction is a cycle of molecular events in which thick myosin
filaments repeatedly attach to and pull on thin actin filaments, so they slide over one another. The actin
filaments are attached to Z discs, each of which marks the end of a sarcomere. The sliding of the
filaments pulls the Z discs of a sarcomere closer together, thus shortening the sarcomere. As this occurs,
the muscle contracts.
Cross-bridge cycle

Cross bridge cycling is a sequence of molecular events that underlies the sliding filament theory.
There are many projections from the thick myosin filaments, each of which consists of two myosin
heads. Each myosin head has binding sites for ATP (or ATP hydrolysis products: ADP and Pi) and actin.
The thin actin filaments also have binding sites for the myosin heads—a cross-bridge forms when a
myosin head binds with an actin filament.

 A cross-bridge cycle begins when the myosin head binds to an actin filament. ADP and Pi are
also bound to the myosin head at this stage.
 Next, a power stroke moves the actin filament inward toward the sarcomere center, thereby
shortening the sarcomere. At the end of the power stroke, ADP and Pi are released from the
myosin head, leaving the myosin head attached to the thin filament until another ATP binds to
the myosin head.
 When ATP binds to the myosin head, it causes the myosin head to detach from the actin
filament. ATP is again split into ADP and Pi and the energy released is used to move the myosin
 head into a "cocked" position. Once in this position, the myosin head can bind to the actin
filament again, and another cross-bridge cycle begins.

Cross-bridge cycling is able to continue as long as there are sufficient amounts of ATP and Ca2+ in the
cytoplasm. Termination of cross-bridge cycling can occur when Ca2+ is actively pumped back into the
sarcoplasmic reticulum. When Ca2+ 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 muscle relaxes. The Ca2+ ions leave the troponin molecule to maintain the
Ca2+ ion concentration in the sarcoplasm. The active pumping of Ca2+ ions into the sarcoplasmic
reticulum creates a deficiency in the fluid around the myofibrils. This causes the removal of Ca2+ ions
from the troponin. Thus, the tropomyosin-troponin complex again covers the binding sites on the actin
filaments and contraction ceases.