BOICHEMISTRY OF MUSCLE ACTION
Excluding reflexes, 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 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. This is a chemical
Synapse where a motor neuron transmits a signal to muscle fiber to initiate a muscle
contraction.
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.
This diagram represents the sequence of events that occurs when a motor neuron stimulates a
muscle fiber to contract. The action potential travels down the t-tubules and excites the
sarcoplasmic reticulum which releases calcium. Calcium when bound to troponin causes
conformational changes in the sarcomere. Consequently, the interaction of thick and thin
filaments of the sarcomere leads to muscle contraction
These events happen very quickly in the world of excitable membranes (think about how
quickly you can snap your fingers as soon as you decide to do it). 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 to diffuse out of
the SR and into the sarcoplasm. It is the arrival of in the sarcoplasm that initiates contraction
of the muscle fiber by its contractile units, or sarcomeres.
Narrow T-tubules permit the conduction of electrical impulses. The SR functions to regulate
intracellular levels of calcium. Two terminal cisternae (where enlarged SR connects to the T-
tubule) and one T-tubule comprise a triad—a “threesome” of membranes, with those of SR
on two sides and the T-tubule sandwiched between them.
Sliding Filament Theory of Muscle Contraction
Once the muscle fiber is stimulated by the motor neuron, actin, and myosin protein filaments
within the skeletal muscle fiber slide past each other to produce a contraction. The sliding
filament theory theory that explains muscle contraction by the sliding of myosin
filaments over actin filaments within muscle fibers is the most widely accepted
explanation for how this occurs. 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.
The top diagram shows a relaxed sarcomere, and the bottom diagram shows a contracted
sarcomere. Please note the z discs, h zone, and M line. In a contracted sarcomere the H zone
reduces as compared to relaxed sarcomere because actin fibers (greenish-yellow double
helix) move towards the M line.
Crossbridge Cycling
Crossbridge 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.
Summary of Events That Lead to Skeletal Muscle Contraction and Relaxation
1. Activation of a somatic motor neuron is normally a voluntary decision that made in
the central nervous system.
2. Propagation of action potentials down the somatic motor neuron axon
3. Depolarization of the axon terminal of the somatic motor neuron, opening of voltage-
gated Ca2+ channels and entry of Ca2+ into the axon terminal.
4. Fusion of synaptic vesicles with the pre-synaptic plasma membrane, and subsequent
release of the neurotransmitter (acetylcholine) at the neuromuscular junction
5. Binding of acetylcholine to the nicotinic acetylcholine receptors located in the plasma
membrane of the skeletal muscle cell. Acetylcholine binding leads to the opening of this
ligand-gated ion channel.
6. Opening of the nicotinic acetylcholine receptor leads to the entry of Na+ into the
myoplasm which leads to depolarization of the plasma membrane (sarcolemma) of the
skeletal muscle cell. This depolarization is referred to as the end-plate potential.
7. At the neuromuscular junction, the end-plate potential is always excitatory and
therefore, leads to the activation of voltage-gated Na+ channels in the sarcolemma.
Activation of voltage-gated Na+ channel leads to the generation of muscle action
potentials that travels along the sarcolemma.
8. Propagation of the action potential deep into the muscle cell down the t-tubules.
9. The depolarization caused by the action potential in the t-tubule changes the
conformation of the dihydropyridine receptor. This change in conformation releases the
plug that normally keeps the sarcoplasmic ryanodine receptors closed.
10. Ryanodine receptors are Ca2+ channels and their opening releases Ca2+ into the
sarcoplasm.
11. Diffusion of calcium to the sarcomere units.
12. Binding of Ca2+ to the troponin complex.
13. Displacement of the troponin-tropomyosin unit to expose the myosin cross-bride
binding site of G-actin.
14. Binding of myosin cross-bridges to the binding sites on G-actin molecules
15. Power stroke of the cross-bridges and movement of the thin filaments over the thick
filaments.
16. Continued cross-bridge cycling for as long as ATP is present and Ca2+
concentration
remain high in the myoplasm.
17. Muscle shortening and /or tension development
18. Muscle relaxation occurs when the train of motor neuron action potentials comes to
an end. In the absence of motor neuron action potentials, no additional muscle action
potentials are generated. The sarcolemma at the level of the t-tubules repolarizes to its
resting value of -90 mV. This repolarization once again places the dihydropyridine plug
over the ryanodine Ca2+ channels (closes it). Thus, no additional Ca2+ enters the
cytoplasm.
19. Calcium concentration in the myoplasm is brought back to normal due to the
activity
of the sarcoplasmic Ca2+-Mg2+ ATPase which pumps Ca2+ back into the sarcoplasmic
reticulum.
20. Reduced Ca2+ in the myoplasm causes the troponin-tropomyosin complex to once
again cover the myosin binding site of actin.
21. The myosin head “waits “in its relaxed state (ADP and Pi bound) for another rise in
the Ca2+ concentration in the myoplasm.
Sources of Energy for muscle contraction: immediate source energy for muscle
contraction is the hydrolysis of ATP. ATP → ADP + Pi+ Energy This can only sustain
contraction for a fraction of time.
A muscle action potential is a brief change in the electrical potential across the membrane of
a muscle cell (myocyte) that occurs when it is stimulated. This electrical signal initiates
muscle contraction by causing the release of calcium ions, which in turn triggers the sliding
filament mechanism.
1. Nerve Impulse and Depolarization:
Muscle contraction begins when a nerve impulse (an action potential) arrives at the motor end
plate (the junction where a motor neuron meets a muscle fiber). This nerve impulse triggers
the release of a neurotransmitter (acetylcholine) into the synapse. The neurotransmitter binds
to receptors on the muscle cell's sarcolemma (plasma membrane), causing it to become more
permeable to sodium ions (Na+). A rapid influx of Na+ into the muscle cell causes a change
in the membrane potential, resulting in depolarization.
2. Action Potential Propagation:
The depolarization initiates an action potential, which is a rapid and transient change in
membrane potential. This action potential propagates (travels) along the sarcolemma,
spreading across the entire muscle cell. The action potential is maintained by the opening and
closing of voltage-gated sodium and potassium channels.
3. Calcium Release and Contraction:
The action potential triggers the release of calcium ions (Ca2+) from the sarcoplasmic
reticulum (a specialized organelle within the muscle cell). The released Ca2+ binds to
troponin, a protein on the thin filaments (actin) of the sarcomere. This binding causes a
conformational change in tropomyosin, another protein that blocks the myosin binding sites
on actin. With the myosin binding sites exposed, the myosin heads can attach to actin and
initiate the sliding filament mechanism, leading to muscle contraction.
4. Repolarization and Relaxation:
After the action potential has passed, the membrane repolarizes as potassium ions (K+) flow
out of the cell. The Ca2+ is then pumped back into the sarcoplasmic reticulum, and the
muscle relaxes.
5. Importance of Action Potentials:
Action potentials are crucial for initiating and propagating signals that lead to muscle
contraction.
They are the primary mechanism by which the nervous system controls muscle activity. The
duration of the action potential and the subsequent muscle twitch can vary depending on the
type of muscle (fast vs. slow). Repetitive firing of action potentials can lead to summation of
contractions, resulting in sustained muscle tension (tetanus).
Muscular Dystrophy
The term muscle fatigue is used to denote a transient decrease in the capacity to perform
physical actions. The following characterize the range of effects ascribed to muscle
fatigue:‘Intensive activity of muscles causes a decline in performance, known as
fatigue.‘Performing a motor task for long periods of time induces motor fatigue, which is
generally defined as a decline in a person's ability to exert force
‘Fatigue is known to be reflected in the EMG signal as an increase of its amplitude and a
decrease of its characteristic spectral frequencies.‘…the sensation of fatigue is the conscious
awareness of changes in subconscious homeostatic control systems
Muscular dystrophy (MD) is a collective group of inherited non-inflammatory but
progressive muscle disorders without a central or peripheral nerve abnormality. The disease
affects the muscles with definite fiber degeneration but without evidence of morphologic
aberrations.
Advances in molecular biology techniques illuminate the genetic basis underlying all types of
MD: defects in the genetic code for dystrophin, a 427-kd skeletal muscle protein (Dp427).
These defects result in the various manifestations commonly associated with MD, such as
weakness and pseudohypertrophy. Dystrophin can also be found in cardiac smooth muscles
and in the brain (accounting for the slight intellectual disability associated with this disease).
Minor variations notwithstanding, all types of MD have in common progressive muscle
weakness that tends to occur in a proximal-to-distal direction, though there are some rare
distal myopathies that cause predominantly distal weakness. The decreasing muscle strength
in those who are affected may compromise the patient's ambulation potential and, eventually,
cardiopulmonary function.
In addition, structural soft-tissue contractures and spinal deformities may develop from poor
posturing caused by the progressive muscle weakness and imbalance, all of which can further
compromise function and longevity.
The mechanism whereby a contractile multinucleated skeletal muscle fiber is linked to the
basement membrane (BM) that ensheaths it represents a paradigm for our understanding of
BM assembly and interactions between the cell and extracellular matrix in the context of
human pathobiology. Multiple matrix proteins, cell-surface receptors, transmembrane
accessory proteins, cytoskeletal linker proteins, and glycosylating enzymes are required for
the establishment and maintenance of the large, integrated complex that tightly links the
myofiber cytoskeleton to the sarcolemma (plasma membrane) and the sarcolemma to the
skeletal muscle BM. Genetic defects that alter the expression, structure, or function of these
proteins cause a devastating class of diseases, the muscular dystrophies.
Muscular dystrophies are characterized by the progressive degeneration and weakness of
skeletal muscle that includes muscle fiber necrosis, regeneration, and fibrosis. The severity
and rate of progression of muscular dystrophy can vary dramatically, from congenital forms
to the more common delayed-onset form known as Duchenne muscular dystrophy. From a
cell biological perspective, muscular dystrophies with a genetic basis can be divided into
types that correspond roughly to the site of the protein or protein complex that is affected by
mutation. Mutations that affect the muscle BM cause congenital muscular dystrophy.
Those that affect the cytoskeletal protein dystrophin cause Duchenne and Becker muscular
dystrophy.
Those that affect transmembrane proteins called sarcoglycans cause limb-girdle muscular
dystrophy.
Interestingly, mutations that impact the enzymes responsible for glycosylation of
dystroglycan cause the dystroglycanopathies, which manifest as muscular dystrophies with
variable degrees of severity and timing of onset, as well as variable CNS and eye defects.
Dystroglycan serves as the functional centerpiece of the dystrophin-glycoprotein complex
that links the cytoskeleton to the BM and, therefore, plays a crucial role in maintaining
skeletal muscle health.
OXYGEN DEBT
When a period of exercise is over, lactic acid must be removed. The body's tolerance of lactic
acid is limited.
Lactic acid is taken to the liver by the blood, and either:
oxidised to carbon dioxide and water, or
converted to glucose, then glycogen - glycogen levels in the liver and muscles can
then be restored
These processes require oxygen. This is why, when the period of activity is over, a person’s
breathing rate and heart rate do not return to normal straightaway.
The amount of oxygen required to remove the lactic acid, and replace the body's reserves of
oxygen, is called the oxygen debt.
When someone who has been exercising pays back an oxygen debt, it can take from a few
hours for normal exercise, to several days after a marathon.
Excess post-exercise oxygen consumption (EPOC, informally called afterburn) is a
measurably increased rate of oxygen intake following strenuous activity. In historical
contexts the term "oxygen debt" was popularized to explain or perhaps attempt to quantify
anaerobic energy expenditure, particularly as regards lactic acid/lactate metabolism. in fact,
the term "oxygen debt" is still widely used to this day . However, direct and indirect
calorimeter experiments have definitively disproven any association of lactate metabolism as
causal to an elevated oxygen uptake
In recovery, oxygen (EPOC) is used in the processes that restore the body to a resting state
and adapt it to the exercise just performed. These include: hormone balancing, replenishment
of fuel stores, cellular repair, innervation, and anabolism. Post-exercise oxygen consumption
replenishes the phosphagen system. New ATP is synthesized and some of this ATP donates
phosphate groups to creatine until ATP and creatine levels are back to resting state levels
again. he EPOC effect is greatest soon after the exercise is completed and decays to a lower
level over time. One experiment, involving exertion above baseline, found EPOC increasing
metabolic rate to an excess level that decays to 13% three hours after exercise, and 4% after
16 hours, for the studied exercise dose. Another study, specifically designed to test whether
the effect existed for more than 16 hours, conducted tests for 48 hours after the conclusion of
the exercise and found measurable effects existed up to the 38-hour post-exercise
measurement, for the studied exercise dose.