C As a result, AChR clusters are concentrated at a high density in the area underneath the nerve terminal maximizing the efficiency of neuromuscular transmission. D Postnatal maturation of AChR clusters and plaque to pretzel transformation. E Fragmentation of AChR clusters with aging. Subsequently, when the motor neurons innervate some of the prepatterned AChR clusters, these become enlarged and stable while aneural AChR clusters tend to disappear, so that the NMJs are eventually formed in the central region of muscle fibers.
By contrast, aneural clusters not stabilized by agrin signaling are dispersed by a negative signal, believed to be driven by the release of ACh from the presynaptic terminal Lin et al. Genes coding for components of the neuromuscular synapse become increasingly expressed in subsynaptic nuclei, resulting in the concentration of proteins required locally at the NMJ Schaeffer et al.
Even before innervation, AChR gene expression is enriched in the central region of embryonic skeletal muscles Lin et al. However, the area of AChR gene expression in muscles lacking motor axons is wider than usual, pointing that neural signals refine muscle-autonomous prepatterning Yang X. One of these signals is likely to be agrin, since compartmentalized expression in subsynaptic nuclei is severely affected in agrin and MuSK deficient mice as shown by in situ hybridization experiments to explore the distribution of AChR subunit mRNAs DeChiara et al.
This does not occur in rapsyn deficient mice where AChR genes are selectively expressed by synaptic nuclei in the absence of AChR clusters Gautam et al. The communication between synaptic signals and targeted transcription is thought to be mediated by specific promoter elements in synaptic genes and E-twenty six ETS transcription factors. In particular, the N-box, a six-base pair element, was identified as a critical element in targeting the transcription of AChR delta Koike et al.
Disruption of this element in mouse models results in widespread expression of the reporter gene throughout the entire muscle fiber. N-box motifs have also been reported to drive synapse-specific expression of utrophin Gramolini et al. Presynaptic differentiation begins after axon formation and culminates with the assembly of the neuromuscular synapse and the differentiation of a functional nerve terminal opposite the specialized postsynaptic membrane, where presynaptic proteins become concentrated.
A relatively recent finding is that LRP4 works as a muscle-derived retrograde signal that controls the early steps of presynaptic differentiation by binding to motor axons and inducing clustering of synaptic vesicles and active zone proteins Yumoto et al. Interestingly, although MuSK overexpression in Lrp4 mutant mice restored AChR clustering, it failed to rescue presynaptic differentiation as motor axons kept growing along the muscle and rarely contacted AChR clusters Yumoto et al.
However, in the absence of these molecules, motor axons manage to contact AChR clusters and differentiate considerably, which suggests that they act at a later stage in presynaptic differentiation compare to LRP4. It is thought that this association leads to clustering of VGCC into arrays, which in turn recruit and stabilize other constituents of the presynaptic apparatus. Neuromuscular junctions are functionally active in the embryonic stage, but they undergo complex postnatal maturation during the first weeks of life including synaptic elimination, endplate remodeling, and the AChR gamma-to-epsilon switch.
During this period, the NMJ increases in size and the sarcolemma develops invaginations called postjunctional folds that increase total surface area. The morphology of the NMJ is changed from oval to a more complex perforated plaque, which in mice is described as pretzel-shaped, with a nearly contiguous arrangement of AChRs. During synapse elimination, all but one axon are gradually withdrawn from multiply innervated muscle fibers, leaving a single innervating axon at each NMJ Lichtman and Colman, This is a competitive and asynchronous process taking place at each endplate where more active synaptic sites destabilize neighboring inactive synapses Balice-Gordon and Lichtman, ; Keller-Peck et al.
Although synaptic activity and in particular spike timing seem to drive synaptic elimination Favero et al. In particular, tSCs have been found to participate in the pruning of developing synapses through the phagocytosis of immature axons and the displacement of nerve terminals from each other and the postsynaptic membrane Smith et al.
However, it is still not clear how this relates to motor neuron activity. Another study showed that loss of glial Neurofascin in mice delays developmental synapse elimination by disrupting neuronal cytoskeletal organization and trafficking pathways in motor axons Roche et al. Other candidates thought to participate in the refining of the neuromuscular circuitry include the major histocompatibility complex, class I MHC-I Tetruashvily et al.
The remodeling of the murine endplates during early postnatal life results in a plaque-to-pretzel transition where the NMJs become perforated and increasingly complex with multiple branches innervated by a single axon Slater, Using cultured aneural myotubes on laminin-coated plates that mimic the in vivo transformation, it was shown that perforations in the AChR aggregates bear structures resembling podosomes whose location and dynamics are spatiotemporally correlated with changes in the topology of AChR clusters Proszynski et al.
Podosomes are adhesive dynamic actin-rich matrix remodeling organelles described in numerous cell types. However, evidence for the relevance of podosomes in vivo is scarce and specifically, there is no definitive proof of the existence of synaptic podosomes at the NMJ in living organisms Bernadzki et al.
The latter is a rho guanine nucleotide exchange factor GEF involved in actin cytoskeletal dynamics. Finally, being significantly smaller and more fragmented than murine NMJs Jones et al.
The apparent macroscopic stability of the NMJ conceals a remarkable molecular dynamism where AChRs are continually exchanged between synaptic and extrasynaptic regions to maintain the high density of AChRs at the postsynaptic membrane Akaaboune et al.
The homeostasis of the neuromuscular synapse throughout life is essential for the NMJ function, as inactivation of the underlying molecular mechanisms results in synaptic disassembly Tezuka et al. They may also have distinct roles in synapse formation and maintenance: for instance, the forced expression of DOK7 in agrin deficient mice restores synapse formation but NMJs disappear rapidly after birth, which points to an additional role of agrin distinct from MuSK activation in postnatal maintenance Tezuka et al.
By contrast, other molecules playing an important role in NMJ stabilization and maintenance are dispensable during synapse formation: some components of the dystrophin-glycoprotein complex DGC Ibraghimov-Beskrovnaya et al.
There is also increasing evidence from clinical Lashley et al. Furthermore, one study in mice proposed that sympathetic neurons make close contact with NMJs Khan et al. The DGC complex links the cytoskeleton of muscle fibers to the extracellular matrix Ibraghimov-Beskrovnaya et al. However, by 1 month of age and independently of muscle changes, AChRs became abnormally distributed with irregular branch borders while the size, number and arrangement of branches remained unaltered Grady et al.
The structural abnormalities seen in the mdx mouse model of Duchenne muscular dystrophy Sicinski et al. However, these are found exclusively at NMJs on regenerated muscle fibers, which indicates that endplate remodeling is related to muscle damage rather than dystrophin deficiency Lyons and Slater, Src family kinases src, fyn, and yes have been implicated in signaling pathways downstream of MuSK Fuhrer and Hall, The neuronal cell adhesion molecule NCAM is thought to participate in the maturation of the presynaptic terminal as NCAM null mice present delayed presynaptic structural maturation and smaller endplates Rafuse et al.
Finally, it is increasingly more evident that glial cells have an important role in NMJ maintenance. In adult frogs, selective ablation of tSCs results in widespread retraction of existing synapses Reddy et al. Injury to the nerve or muscle, lack of physical activity and ageing can alter synaptic organization resulting in endplate fragmentation, partial denervation and reduction in active zones and AChR density Stanley and Drachman, ; Lyons and Slater, ; Valdez et al.
It is well known that mouse muscle endplates lose the normal pretzel shape and become fragmented with multiple spot contacts following muscle fiber damage Lyons and Slater, One of the best examples is the mdx mouse model of Duchenne muscular dystrophy Sicinski et al.
In 8-week old mdx mice, muscle endplates from regenerating fibers appear dramatically fragmented over an enlarged postsynaptic area and nerve terminals display abnormally complex features, with a significant increase in the number of fine terminal arborizations, many bearing bouton-like swellings Lyons and Slater, The alterations seen in the mdx mouse increase with ageing, probably as a consequence of recurrent muscle damage Torres and Duchen, Interestingly, the structural changes do not alter the safety margin of neuromuscular transmission Nagel et al.
Therefore, the significance of this process is not fully understood as this could be the outcome of a physiological mechanism of NMJ maintenance rather than synapse degeneration Slater, Endplate reinnervation following nerve injury results in degradation of junctional AChRs, increase of their turnover rates and structural changes to the NMJ Stanley and Drachman, ; Rich and Lichtman, ; Akaaboune et al.
Other key elements of synapse development such as Col13a1 Zainul et al. Finally, tSCs play a key role in reinnervation by guiding axons through the extension of their processes Son and Thompson, and retracting processes from territory they previously occupied within the endplate Kang et al.
PR reviewed the literature and drafted the manuscript. JC and DB contributed to critical revision of the manuscript for important intellectual content. AV contributed to critical revision of the manuscript for important intellectual content and senior authorship.
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Skeletal muscle cell contraction occurs after a release of calcium ions from internal stores, which is initiated by a neural signal. Each skeletal muscle fiber is controlled by a motor neuron, which conducts signals from the brain or spinal cord to the muscle. The following list presents an overview of the sequence of events involved in the contraction cycle of skeletal muscle:. We stimulate skeletal muscle contraction voluntarily. Electrical signals from the brain through the spinal cord travel through the axon of the motor neuron.
The axon then branches through the muscle and connects to the individual muscle fibers at the neuromuscular junction. The folded sarcolemma of the muscle fiber that interacts with the neuron is called the motor end-plate; the folded sarcolemma increases surface area contact with receptors. The ends of the branches of the axon are called the synaptic terminals, and do not actually contact the motor end-plate.
A synaptic cleft separates the synaptic terminal from the motor end-plate, but only by a few nanometers. Communication occurs between a neuron and a muscle fiber through neurotransmitters. Neural excitation causes the release of neurotransmitters from the synaptic terminal into the synaptic cleft, where they can then bind to the appropriate receptors on the motor end-plate.
The motor end-plate has folds in the sarcolemma, called junctional folds, that create a large surface area for the neurotransmitter to bind to receptors. Generally, there are many folds and invaginations that increase surface area including junctional folds at the motor endplate and the T-tubules throughout the cells. The neurotransmitter acetylcholine is released when an action potential travels down the axon of the motor neuron, resulting in altered permeability of the synaptic terminal and an influx of calcium into the neuron.
The calcium influx triggers synaptic vesicles, which package neurotransmitters, to bind to the presynaptic membrane and to release acetylcholine into the synaptic cleft by exocytosis. The balance of ions inside and outside a resting membrane creates an electric potential difference across the membrane.
This means that the inside of the sarcolemma has an overall negative charge relative to the outside of the membrane, which has an overall positive charge, causing the membrane to be polarized.
Once released from the synaptic terminal, acetylcholine diffuses across the synaptic cleft to the motor end-plate, where it binds to acetylcholine receptors, primarily the nicotinic acetylcholine receptors. This binding causes activation of ion channels in the motor end-plate, which increases permeability of ions via activation of ion channels: sodium ions flow into the muscle and potassium ions flow out. Both sodium and potassium ions contribute to the voltage difference while ion channels control their movement into and out of the cell.
This reduces the voltage difference between the inside and outside of the cell, which is called depolarization. As acetylcholine binds at the motor-end plate, this depolarization is called an end-plate potential.
It then spreads along the sarcolemma, creating an action potential as voltage-dependent voltage-gated sodium channels adjacent to the initial depolarization site open. The action potential moves across the entire cell membrane, creating a wave of depolarization. After depolarization, the membrane needs to be returned to its resting state. This is called repolarization, during which sodium channels close and potassium channels open.
During repolarization, and for some time after, the cell enters a refractory period, during which the membrane cannot become depolarized again.
This is because in order to have another action potential, sodium channels need to return to their resting state, which requires an intermediate step with a delay.
Propagation of an action potential and depolarization of the sarcolemma comprise the excitation portion of excitation-contraction coupling, the connection of electrical activity and mechanical contraction. The structures responsible for coupling this excitation to contraction are the T tubules and sarcoplasmic reticulum SR.
The T tubules are extensions of the sarcolemma and thus carry the action potential along their surface, conducting the wave of depolarization into the interior of the cell. T tubules form triads with the ends of two SR called terminal cisternae. When tropomyosin moves, the myosin binding site on the actin is uncovered.
Low sarcoplasmic calcium levels prevent unwanted muscle contraction. Acetylcholine , often abbreviated as ACh, is a neurotransmitter released by motor neurons that binds to receptors in the motor end-plate. It is an extremely important small molecule in human physiology.
On the neuron side of the synaptic cleft, there are typically , vesicles waiting to be exocytosed at any time and each vesicle contains up to 10, molecules of acetylcholine.
ACh is produced by the reaction of Acetyl coenzyme A CoA with a choline molecule in the neuron cell body. After it is packaged, transported, and released, it binds to the acetylcholine receptor on the motor end-plate; it is degraded in the synaptic cleft by the enzyme acetylcholinesterase AChE into acetate and acetic acid and choline.
The choline is recycled back into the neuron. AChE resides in the synaptic cleft, breaking down ACh so that it does not remain bound to ACh receptors, which would interrupt normal control of muscle contraction. In some cases, insufficient amounts of ACh prevent normal muscle contraction and cause muscle weakness. Botulinum toxin prevents ACh from being released into the synaptic cleft.
With no ACh binding to its receptors at the motor end-plate, no action potential is produced, and muscle contraction cannot occur.
Botulinum toxin is produced by Clostridium botulinum , a bacterium sometimes found in improperly canned foods. Ingestion of very small amounts can cause botulism, which can cause death due to the paralysis of skeletal muscles, including those required for breathing.
ATP supplies the energy for muscle contraction to take place. Muscle contraction does not occur without sufficient amounts of ATP. The amount of ATP stored in muscle is very low, only sufficient to power a few seconds worth of contractions. As it is broken down, ATP must therefore be regenerated and replaced quickly to allow for sustained contraction. One ATP moves one myosin head one step. This can generate three picoNewtons pN of isometric force, or move 11 nanometers.
Three pN is a very small force—a human bite, generated by muscle, can generate trillion pN of force. And 11 nm is a very small distance— one inch has 25 million nanometers. There are three mechanisms by which ATP can be regenerated: creatine phosphate metabolism, anaerobic glycolysis, and aerobic respiration. Creatine phosphate is a phosphagen, which is a compound that can store energy in its phosphate bonds.
In a resting muscle, excess ATP adenosine triphosphate transfers its energy to creatine, producing ADP adenosine diphosphate and creatine phosphate. When the muscle starts to contract and needs energy, creatine phosphate and ADP are converted into ATP and creatine by the enzyme creatine kinase. This reaction occurs very quickly; thus, phosphagen-derived ATP powers the first few seconds of muscle contraction. However, creatine phosphate can only provide approximately 15 seconds worth of energy, at which point another energy source has to be available.
Glycolysis is an anaerobic process that breaks down glucose sugar to produce ATP; however, glycolysis cannot generate ATP as quickly as creatine phosphate. The sugar used in glycolysis can be provided by blood glucose or by metabolizing glycogen that is stored in the muscle. Each glucose molecule produces two ATP and two molecules of pyruvate, which can be used in aerobic respiration or converted to lactic acid.
If oxygen is available, pyruvic acid is used in aerobic respiration. However, if oxygen is not available, pyruvic acid is converted into lactic acid, which may contribute to muscle fatigue and pain. This occurs during strenuous exercise when high amounts of energy are needed but oxygen cannot be delivered to muscle at a rate fast enough to meet the whole need. Anaerobic glycolysis cannot be sustained for very long approximately one minute of muscle activity , but it is useful in facilitating short bursts of high-intensity output.
Glycolysis does not utilize glucose very efficiently, producing only two ATP molecules per molecule of glucose, and the by-product lactic acid contributes to muscle fatigue as it accumulates. Lactic acid is transported out of the muscle into the bloodstream, but if this does not happen quickly enough, lactic acid can cause cellular pH levels to drop, affecting enzyme activity and interfering with muscle contraction.
Aerobic respiration is the breakdown of glucose in the presence of oxygen to produce carbon dioxide, water, and ATP. Aerobic respiration in the mitochondria of muscles uses glycogen from muscle stores, blood glucose, pyruvic acid, and fatty acids. Approximately 95 percent of the ATP required for resting or moderately active muscles is provided by aerobic respiration.
Aerobic respiration is much more efficient than anaerobic glycolysis, producing approximately 38 ATP molecules per molecule of glucose. However, aerobic respiration does not synthesize ATP as quickly as anaerobic glycolysis, meaning that the power output of muscles declines, but lower-power contractions can be sustained for longer periods. Muscles require a large amount of energy, and thus require a constant supply of oxygen and nutrients. Blood vessels enter muscle at its surface, after which they are distributed through the entire muscle.
Blood vessels and capillaries are found in the connective tissue that surrounds muscle fascicles and fibers, allowing oxygen and nutrients to be supplied to muscle cells and metabolic waste to be removed. Myoglobin, which binds oxygen similarly to hemoglobin and gives muscle its red color, is found in the sarcoplasm. This combination of different energy sources is important for different types of muscle activity. As an analogy, a cup of coffee with lots of sugar provides a quick burst of energy but not for very long.
A balanced meal with complex carbohydrates, protein and fats takes longer to impact us, but provides sustained energy. After the first few seconds of exercise, available ATP is used up. After the next few minutes, cellular glucose and glycogen are depleted. After that time, fatty acids and other energy sources are used to make ATP.
Sometimes, time is important. You have already learned about the anatomy of the sarcomere,with its coordinated actin thin filaments and myosin thick filaments. For a muscle cell to contract, the sarcomere must shorten in response to a nerve impulse. The thick and thin filaments do not shorten, but they slide by one another, causing the sarcomere to shorten while the filaments remain the same length.
This process is known as the sliding filament model of muscle contraction. The mechanism of contraction is accomplished by the binding of myosin to actin, resulting in the formation of cross-bridges that generate filament movement. When a sarcomere shortens, some regions shorten while others remain the same length. A sarcomere is defined as the distance between two consecutive Z discs or Z lines. When a muscle contracts, the distance between the Z discs is reduced.
The H zone, the central region of the A zone, contains only thick filaments and shortens during contraction. The I band contains only thin filaments and also shortens. The A band does not shorten; it remains the same length, but A bands of adjacent sarcomeres move closer together during contraction. Thin filaments are pulled by the thick filaments towards the center of the sarcomere until the Z discs approach the thick filaments.
The zone of overlap, where thin filaments and thick filaments occupy the same area, increases as the thin filaments move inward. The ideal length of a sarcomere to produce maximal tension occurs when all of the thick and thin filaments overlap. If a sarcomere is stretched past this ideal length, some of the myosin heads in the thick filaments are not in contact with the actin in the thin filaments, and fewer cross-bridges can form. This results in fewer myosin heads pulling on actin, and less tension is produced.
If a sarcomere is shortened, the zone of overlap is reduced as the thin filaments reach the H zone, which is composed of myosin tails. Because myosin heads form cross-bridges, actin will not bind to myosin in this zone, again reducing the tension produced by the muscle. If further shortening of the sarcomere occurs, thin filaments begin to overlap with each other, further reducing cross-bridge formation and the amount of tension produced.
If the muscle were stretched to the point where thick and thin filaments do not overlap at all, no cross-bridges are formed, and no tension is produced. This amount of stretching does not usually occur, as accessory proteins and connective tissue oppose extreme stretching. With large numbers of relatively weak molecular motors, we can more easily adjust the force to meet our needs. Otherwise, we would regularly be producing too little or too much force for most of our tasks. Also, molecules are only capable of generating small forces based on their molecular structure.
You have already learned about how the information from a neuron ultimately leads to a muscle cell contraction. One action potential in a motor neuron produces one contraction. This contraction is called a twitch. A single twitch does not produce any significant muscle contraction. Multiple action potentials repeated stimulation are needed to produce a muscle contraction that can produce work.
A twitch can last from a few milliseconds up to milliseconds, depending on the muscle type.
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