What Stimulates a Skeletal Muscle Cell to Contract?

Skeletal Musculus Cell

In cultured skeletal muscle cells and C2C12 myotubes, Ucn 2 inhibits insulin-induced Akt and ERK1/2 phosphorylation, consequent with the hypothesis that Ucn 2 functions as a local negative regulator of glucose uptake in skeletal muscle and suggests the possibility that suppression of the Ucn 2/CRH-R2 pathway may provide benefits in insulin-resistant states such every bit blazon 2 diabetes.

From: Reference Module in Neuroscience and Biobehavioral Psychology , 2017

Myokines: A potential central factor in evolution, treatment, and biomarker of sarcopenia

Wataru Aoi , in Sarcopenia, 2021

Abstract

Skeletal muscle cells secrete various proteins/peptides, known every bit myokines, into the extracellular milieu. The concept of myokines could be expanded to minor peptides, noncoding RNAs, and metabolites and applied to various fields including sports, health promotion, and medicine. Myokines tin regulate functions such as energy metabolism, anti-inflammation, and muscle hypertrophy via autocrine, paracrine, and endocrine furnishings. Many myokines are secreted in response to practise and musculus contraction, while their secretion is dysregulated in conditions such as aging and physical inactivity. Accumulating evidence suggests that several myokines regulate myogenesis and protein metabolism, which are associated with the development of sarcopenia. Some myokines may have the potential to exist developed every bit biomarkers for sarcopenia. Agreement the role of myokines might provide insights into the mechanism and treatment of sarcopenia.

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Stem cell and cistron therapy for cardiac regeneration

East. Yaniz-Galende , R.J. Hajjar , in Cardiac Regeneration and Repair, 2014

16.2.1 Skeletal myoblasts

Skeletal muscle cells were the first prison cell type to exist used for clinical cell therapy to replace the damaged centre after myocardial infarction (MI). Skeletal muscle cells or satellite cells have been widely studied because of their ease of procurement, autologous origin, growth potential, myogenic commitment and resistance to ischemia. Several studies have demonstrated a beneficial effect of skeletal myoblasts transplantation inside injured myocardium (Murry et al., 1996; Menasche, 2004; Laflamme and Murry, 2005). An improvement in survival, left ventricular (LV) function performance and cardiac regeneration was detected, during brusk-term follow up, later on skeletal myoblast injection following MI (Taylor et al., 1998). In contrast to these reports, other studies failed to prove an improvement in regional or global LV office later on myoblast transplantation in patients with severe ischemic center disease (Menasche et al., 2008). Knockdown of Connexin 43 and Due north-cadherin expression in the injected skeletal myoblasts led to a lack of integration of skeletal myoblasts within the middle and the absence of mechanical or electrical coupling betwixt the engrafted skeletal muscle stalk cells and the myocardium. These findings, together with the potential commitment of skeletal muscle stem cells to get non-contractile skeletal myocytes instead of transdifferentiating into cardiomyocytes, could be the reason for the arrhythmias detected in patients treated with skeletal myoblasts. Additionally, skeletal myoblasts need to be amplified in vitro, leading to their senescence and express proliferation capacity after injection in the injured myocardium (Reinecke et al., 2000, 2004; Hagege et al., 2006; Menasche et al., 2008). Therefore, the potential utilise of skeletal myoblasts every bit targets for cardiac repair remains a business organisation because they are non the nigh suitable prison cell type for cardiac regeneration. To yield more successful results, information technology is necessary to optimize cell transfer methods, prison cell blazon choice, dose administered, survival and engraftment of the transplanted cells within the centre to maintain the same functional and structural properties of the injured myocardium.

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Skeletal Musculus

Clara Franzini-Armstrong , Andrew G. Engel , in Musculus, 2012

Golgi and Associated Organelles

Skeletal muscle cells maintain an extensive and highly differentiated membrane system and in addition they are actively secretory, beingness responsible for the production and secretion of numerous endocrine, autocrine, and bioactive factors (44). It is thus not surprising that musculus fibers have very extensive Golgi systems, the organelles responsible for "maturation" and trafficking of intrinsic membrane proteins and of secretary products. Golgi complexes of skeletal muscle are located in paranuclear areas and in other small-scale portions of the cytoplasm that are not filled by myofibrils, Interestingly, immunolabeling for Golgi system poly peptide markers reveals an anarchistic distribution of multiple small organelles scattered in numerous sites rather than the more conventional unmarried large complex (Figure 53.viii). Additionally, the distribution of Golgi elements is strongly fiber-blazon-dependent (35,45,46). A very extensive microtubule network is related to Golgi distribution.

The SR of muscle fibers is a differentiated domain of the general ER and derives from it past proliferation and differentiation into specific domains dedicated to calcium handling, concurrent with the accumulation of a high density of SR-specific proteins, a subtract in housekeeping proteins and the association with the myofibrils and transverse tubules (47,48). The gradual differentiation starts in parallel with early myofibrillogenesis, with the early formation of CRUs at the cobweb edge and later in the triads (49,50). Generic ER mostly remains located within small spaces in paranuclear positions, in association with the Golgi organization, simply general ER proteins are not excluded from the myofibrils-associated SR, demonstrating functional continuity inside the entire endo-membrane organisation (51,52). Non-musculus cells besides have some domains of the endoplasmic reticulum, the then-chosen calciosomes, that are basically equivalent to the SR in that they have calcium ATPase in the membrane and some calsequestrin (or calreticulin) in the lumen and thus are dedicated to calcium uptake (53). However, these domains are very small-scale.

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Tissues

Bruce Thou. Carlson Doctor, PhD , in The Man Body, 2019

Skeletal Muscle

Skeletal muscle cells occur in the course of multinucleated fibers that can be up to several centimeters long. In the embryo, a skeletal musculus cobweb begins equally a unmarried prison cell, chosen a myoblast. Private myoblasts begin to fuse with one another, forming elongated cells, called myotubes, in which dozens of nuclei are lined up in a fundamental row (Fig. ii.23). The nuclei are large, somewhat elongated and contain a large nucleolus—a characteristic of a cell that is producing big amounts of RNA and proteins. These nuclei and the RNAs that they produce stimulate the synthesis of long contractile proteins that go organized into functional arrays, called sarcomeres, located effectually the periphery of the myotube. Over time, longitudinal series of sarcomeres develop the power to crusade the developing myotube to contract weakly. As the myotube fills with newly synthesized contractile proteins, the myonuclei movement to the periphery of what is now called a muscle fiber.

Figure 2.23. Embryonic development of a skeletal muscle fiber from a myogenic jail cell. Many myoblasts fuse to class a single myotube, which then matures to become a musculus cobweb.

From Carlson (2007), with permission.

Skeletal muscle fibers make and secrete basal lamina material, which completely surrounds the musculus fibers and mediates the transmission of contractions of the muscle fibers to the surrounding connective tissue. Situated between a musculus cobweb and its basal lamina is an undistinguished looking mononuclear cell, called a satellite jail cell, that is distinguishable from myonuclei only under the electron microscope or with special stains (Fig. 2.24). Satellite cells serve as stem cells for skeletal muscle fibers and are necessary for both their growth and regeneration. Multinucleated cells (syncytia) exercise not divide, and few muscle fibers form de novo afterward birth. Therefore for a muscle to grow after nascence, the musculus fibers must add new nuclei derived from dividing satellite cells in order to increase in both length and girth.

Effigy 2.24. Cartoon of a satellite cell of a skeletal musculus fiber. Mononuclear satellite cells are situated between a muscle fiber and its basal lamina. They serve as developed stem cells for the growth and regeneration of the muscle fiber.

Details of both the fine structure and contractile physiology of skeletal muscle fibers are presented in Chapter five. Skeletal muscle fibers are not all homogeneous in either construction or function. Functionally, the speed of their contraction allows them to be divided into 2 main categories— fast and slow. Based on their need for oxygen while contracting, two types of fast muscle fibers have been described. Fast glycolytic fibers, which get their energy by the anaerobic breakup (through a pathway not requiring oxygen) of glycogen, are those used in heavy lifting or in sprinting. Fast oxidative muscle fibers comprise more mitochondria than fast glycolytic fibers and come into play where repeated contractions over a longer period of time is required. Fast oxidative muscle fibers are prominent in individuals trained for repetitive exercise, such as long-distance running. All muscle fibers are surrounded by loose networks of capillaries, but because of the need for continuous metabolic exchange, the capillary network surrounding fast oxidative muscle fibers is more extensive than that surrounding fast glycolytic musculus fibers.

Slow muscle fibers are thinner than fast musculus fibers. They contain more mitochondria and are enwrapped by denser networks of capillaries. These muscle fibers are non equally strong as fast muscle fibers, just they can contract for much longer periods of time and are therefore endurance fibers. Tiresome musculus fibers predominate in postural muscles, a good example existence the soleus muscle in the dogie.

Some animals take fast and slow muscles—for case, dark meat (irksome) and white meat (fast) in chickens. The nighttime color is largely due to the presence of an oxygen-binding protein, myoglobin, which is found in slow muscle fibers. Muscles of American jackrabbits, which specialize in long-distance running, contain a loftier proportion of fast oxidative and slow muscle fibers, whereas cottontail rabbits (hares in Europe), which run in curt fast bursts, are endowed with large numbers of fast glycolytic musculus fibers. Muscles of humans and dogs, on the other hand, contain mixtures of fast and irksome muscle fibers, although their proportions vary from ane muscle to another, depending upon their functional requirements.

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Myology

M. Navarro , ... A. Carretero , in Morphological Mouse Phenotyping, 2017

The Skeletal Muscle Fiber

Skeletal muscle cells or fibers are highly elongated cells with a very rubberband and resistant plasma membrane, called the sarcolemma. Fibers are characterized past the presence of numerous nuclei located at the periphery of the cell, hence musculus fibers are described every bit a syncytium. These cells present a large number of myofibrils ( Figs. iv-two and 4-3 ). Myofibrils are divided into contractile units, or sarcomeres, that are delimited by Z lines, giving the typical striated appearance of the musculus cobweb. Within the sarcomeres at that place are thick myosin and sparse actin myofilaments, which are responsible for muscle wrinkle ( Fig. 4-3 ). Thin myofilaments consist mainly of F-actin ( Fig. four-two ) and other associated proteins (troponin, tropomyosin) and are anchored in the Z line, which is rich in α-actin. Other proteins are as well found in the Z line, such as desmin ( Fig. 4-two ), which helps maintain the structural and mechanical integrity of the cell, connecting the sarcomere to the sarcolemma and other subcellular structures. Each thick myofilament is formed by several myosin molecules ( Figs. 4-2 and four-3 ), each of which consists of two heavy bondage in turn associated with two calorie-free bondage. The myosin filaments are anchored in the eye of the sarcomere at the G line. The cardinal zone of the sarcomere (the A band), where the myosin is situated, is darker (electron-dumbo) in manual electron microscopy. By contrast, the expanse which contains only actin (the I band), presents a more than articulate or electron-lucent appearance ( Fig. 4-3 ). The H band is the expanse at the center of the A band where there is merely myosin ( Fig. 4-2 ). In the rest of the A band the actin and myosin filaments are intertwined ( Fig. 4-3 ). In this zone, the motion of the myosin heads slides actin filaments towards the centre of the sarcomere, thereby shortening the sarcomere and the musculus cobweb to generate force.

Depending on their rate of wrinkle, biochemistry and ultrastructure, two basic types of skeletal musculus fiber can exist delineated: boring twitch fibers (type I) and fast twitch fibers (type Ii). Moreover, blazon Ii fibers tin be subdivided into subtypes such every bit IIA, IIB and intermediates, depending on their content in myosin heavy concatenation isoforms. Type I fibers utilize oxidative phosphorylation as a source of free energy and therefore have more mitochondria ( Figs. 4-4 and 4-five ). Muscles with type I fibers contract more than slowly and are more resistant to fatigue. Tiresome-twitch fibers are also more vascularized and shop more lipids and myogloblin in the sarcoplasm. This, coupled with the relatively reduced density of myofibrils, gives a more blood-red colour to the muscle. By contrast, Type Two fibers use in full general, anaerobic metabolism to generate ATP. Ultrastructurally, blazon II fibers contain more glycogen granules and have less mitochondria and lipid droplets than blazon I fibers ( Figs. 4-4 and 4-5 ). Therefore, muscles that contain mainly type Two fibers have a whitish color. In fact, muscles are composed of a mixture of fiber types, being a mosaic of both type I and blazon II fibers. The percentage of blazon I and II fibers in the same musculus may vary over time, changing from tiresome to fast, or vice versa, depending on the degree of exercise.

Anti-myosin wearisome or anti-myosin fast concatenation antibodies can exist used to differentiate type I and type Ii fibers, respectively ( Fig. 4-four ). In addition, type I and Two fibers can be distinguished by preincubation at acidic pH which inhibits the activity of myosin ATPase in the type 2 fibers ( Fig. iv-four ). Succinate dehydrogenase (SDH) and the reduced form of nicotinamide adenine dinucleotide (NADH) can as well be used to place the oxidative potential of muscle fibers, which is higher in blazon I fibers ( Fig. 4-5 ). These histochemical techniques marking mitochondria in the sarcoplasm of muscle fibers ( Fig. 4-5 ). Mitochondria inside muscle fibers tin likewise be visualized straight by transmission electron microscopy and by the use of fluorescent probes that accumulate in functional mitochondria (for example MitoTracker®) ( Fig. 4-5 ). The glycolytic activity of muscle fibers is hands identified by visualizing the activity of glycerol-phosphate dehydrogenase (GPDH). Type II fibers not only take more GPDH activity, but likewise a greater accumulation of glycogen which can exist visualized by PAS staining ( Fig. 4-6 ).

Musculus fibers are formed by the fusion of myoblasts, some of which remain in the mature muscle as undifferentiated cells known as satellite cells ( Fig. iv-7 ). These cells are responsible for muscle repair and muscle development after nativity. Satellite cells are located beneath the basal lamina, but overlying the muscle fibers, and are thus in straight contact with the sarcolemma of muscle fibers. Satellite cells have very niggling cytoplasm and a nucleus distinguished by the presence of abundant heterochromatin ( Fig. 4-7 ). They express specific markers, such every bit the transcription factor Pax7, which are not expressed in the nuclei of mature muscle fibers ( Fig. 4-seven ).

To produce muscle fiber contraction, calcium needs to be released into the sarcoplasm. Calcium is stored in the terminal cisternae of the sarcoplasmic reticulum bound to the acidic protein calsequestrin ( Fig. 4-8 ). Sarcoplasmic reticulum cisternae are in contact with invaginations of the sarcolemma called T tubules, where they form structures known as triads. These are located between the A and I bands of musculus fibers ( Fig. iv-8 ). T tubules can exist hands identified in manual electron microscopy, or by using an anti-GLUT4 antibody, the most of import glucose transporter in the muscle cobweb ( Fig. 4-8 ). Skeletal musculus plays a crucial role in maintaining claret glucose. Muscle uses glucose for free energy during contractile activity and represents the almost important tissue for glucose uptake and metabolism during the postprandial flow. At rest, GLUT4 is stored in tubulo-vesicular structures located around the nucleus, mainly in the Golgi complex. When stimulated past muscle contractions and/or insulin, GLUT4 is translocated to the plasma membrane and T tubules ( Fig. iv-8 ).

Skeletal muscles are supplied by arteries and veins that enter and leave the muscle abdomen at the level of one or more hilum (plural: hila). Muscular arteries eventually class a capillary plexus, which surrounds each of the muscle fibers, although the distribution of the capillary plexus is not equal for each fiber forming the muscle, as capillary density depends on the musculus cobweb type ( Fig. 4-nine ). Type I fibers are aerobic and are more than vascularized than type Ii fibers, which are anaerobic. For visualization, the capillary endothelial cells of mouse musculus may exist labeled with an anti-PECAM-1 (CD31) antibody.

Skeletal muscle is innervated by motor neurons which originate in the brain (cranial nerves) and the spinal cord (spinal nerves). Each muscle cobweb is innervated past at least one motor neuron axon. The site of contact between the muscle fiber and the axon is a specialized synaptic junction called the motor end-plate, which is responsible for the release of the neurotransmitter acetylcholine ( Fig. 4-9 ). Each motor axon branches earlier reaching the end-plate contact with each musculus fiber, thereby forming several coordinated axon terminals on adjacent muscle fibers ( Fig. 4-ix ). This prepare of muscle fibers that are innervated by a single axon is called a motor unit. Musculus fibers act according to the law of «all or nothing», that is they are contracted or relaxed, with no intermediate states betwixt contraction or relaxation. Therefore, the caste of contraction of a muscle depends on the number of muscle fibers that are simultaneously contracted, that is, the number of motor units that are activated.

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Cytoskeleton

In Medical Cell Biology (Third Edition), 2008

The Functional Unit of Skeletal Muscle Is the Sarcomere

Each skeletal musculus cell, or myofiber, contains many bundles of regularly arranged filaments, chosen myofibrils. It is the highly structured arrangement of filaments within the myofibrils that requite skeletal musculus its characteristic striped or striated advent. Skeletal muscle is the best biological case of the relation of structure, equally viewed through the microscope, with part. Longitudinal sections of skeletal musculus, viewed under the light and electron microscopes, demonstrate an ordered banding blueprint (Fig. iii-2). These are chosen the A band, I band, and the Z disk or Z line.

Effigy three-2. Electron microscopy of skeletal musculus. A longitudinal section through a skeletal muscle cell demonstrates the regular pattern of cross-striations derived from the myofibrils. As shown in this low-magnification electron micrograph, the skeletal-muscle jail cell has many myofibrils aligned in parallel. In this repeating construction, one can easily discern the Z disk. Scale bar = 0.3 μm for A, I, and H bands and G line of the sarcomere. (inset) Terminal cisternae of the sarcoplasmic reticulum (SR) and associated transverse tubule (T).

(Courtesy Dr. Phillip Fields.)

The A ring is the night-staining region of the myofilaments, and it contains the thick filaments, composed of the protein myosin II, as well as overlapping thin filaments. The lite-staining I ring contains the thin filaments, of which the chief protein component is actin. The Z disk appears equally a night line that bisects the I band. In electron micrographs of skeletal muscle, the dark-staining A band is observed to take singled-out regions, termed the H band and Chiliad line. The H band is a zone of lighter staining inside the primal region of the A band, which is bisected past a dark-staining G line. This region of the A band is where the assembly of the myosin thick filaments occurs.

The segment of the myofibril between 2 Z disks, containing a complete A band and two halves of adjoining I band regions, is chosen the sarcomere. The sarcomere is the functional contractile unit of the myofibril. The myosin thick filaments mark the A band, which is equidistant from the two Z disks of the sarcomere. The thin filaments of the sarcomere are joined to the Z disk and extend through the light-staining I ring region and partially into the A ring, where they interdigitate with the myosin thick filaments. The Z disk functions to anchor the thin filaments of the sarcomere. Cross sections through dissimilar portions of the sarcomere provide boosted information about the organization of the thick and thin filaments (see Fig. 3-1). A cantankerous department through the I ring shows simply thin filaments, arranged in a hexagonal blueprint. A section through the H zone of the A ring demonstrates simply thick filaments, whereas a section through the Chiliad ring zone of the A band shows a network of coiled filaments, representing the assembly of the bipolar myosin thick filaments. The segment of the A band at which the thin filaments interdigitate with the myosin thick filaments shows that each thick filament is surrounded by six thin filaments. This arrangement of thick and thin filaments is an essential structural feature of the sarcomere and is required for the sliding of filaments during contraction.

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Molecular Motors and Move

M. Irving , in Comprehensive Biophysics, 2012

4.eleven.4 The Isometric Twitch: Unitary Response of an Intact Muscle Jail cell

Most skeletal muscle cells in vertebrates and almost all those in mammals have an all-or-none response to electric stimulation called a twitch. Thus each activity potential in a motor nerve terminal at the neuromuscular junction produces an activity potential in the muscle cell, which quickly propagates both along and into the muscle prison cell, where it triggers release of calcium ions. The result is to elevate the intracellular Ca ²⁺ ion concentration, [Ca²⁺]_i, synchronously throughout the muscle cobweb volume. [Ca²⁺]_i peaks at about 10 μM virtually x   ms after electric stimulation (Figure iv(a)), then starts to decline as Caⁱⁱ⁺ ions get bound to cellular components and are pumped back into the sarcoplasmic reticulum. The unabridged duration of the [Ca²⁺]_i transient, measured from the half-time of the rising phase to that of the falling phase, is simply nigh 25   ms nether the standard conditions considered hither (amphibian musculus, 4   °C).

Figure four. The relationship betwixt isometric force and intracellular free Ca^two+ concentration [Caⁱⁱ⁺]_i. (a) Temporal relationship between [Ca²⁺]_i (faster) and isometric force (slower) transients following unmarried action potential stimulation in an intact fiber from frog musculus in standard weather (sarcomere length 2.2 μm, 4   °C). (b) Steady-state relationship between relative force and pCa=(–log₁₀ [Ca²⁺]) in a skinned fiber from rabbit psoas musculus, 10   °C; the line is the Hill equation with parameters pCa₅₀=6.0 and n _H=2.vii. Function (a) Dominicus, Y.-B.; Lou, F.; Edman, G. A. P. The relationship between the intracellular Ca²⁺ transient and the isometric twitch forcefulness in frog musculus fibres. Exp. Physiol. 1996, 81, 711–724, with permission from Wiley; part (b) is replotted from the data of Sun, Y.-B.; Brandmeier, B.; Irving, Thou. Structural changes in troponin in response to Caⁱⁱ⁺ and myosin binding to thin filaments during activation of skeletal muscle. Proc. Natl. Acad. Sci. USA 2006, 103, 17771–17776, with permission from PNAS.

The force response to a unmarried activeness potential – the twitch – is much slower than the [Caⁱⁱ⁺]_i transient. No force is detected for the outset ∼10   ms, the and so-called latent period which roughly corresponds to the ascension phase of the [Ca²⁺]_i transient (Figure 4(a)). Higher resolution force recordings testify that forcefulness actually decreases during this latent period (i.e.,. that part of the resting force is lost), in a phenomenon called latency relaxation, before agile forcefulness develops. The origin of this phenomenon is unclear, simply it may be related to a viscoelastic belongings of resting muscle that is lost on activation. When the length of the muscle fiber is held abiding – referred to every bit an isometric contraction – forcefulness reaches its half maximum value near 50   ms later on the action potential.

The pass up of isometric force during the relaxation phase of the twitch has an even longer delay behind the falling phase of the [Ca^two+]_i transient (Figure 4(a)), although the human relationship is complicated by the fact that the final ∼ten% of the recovery of [Ca²⁺]_i is much slower than the master component. Moreover, mechanical relaxation occurs in two distinct phases. In the get-go stage, called 'isometric relaxation′ the lengths of sarcomeres forth the musculus fiber remain shut to their values at the pinnacle of the twitch. When the force has typically declined to about one-half the summit value, the relaxation rate accelerates, and the second phase of relaxation has a roughly exponential time course. This stage is called cluttered relaxation, because it is accompanied by large changes in local sarcomere length, and so that some fiber segments shorten while others are stretched.

Nearly experimental studies of muscle function have attempted to separate contractile and regulatory mechanisms. Studies focused on contractile mechanisms are more often than not carried out at an intracellular Ca²⁺ concentration that is sufficiently high to saturate the Ca²⁺ binding sites on troponin. In intact musculus cells, this can be accomplished past applying a rapid train of electrical stimuli called a tetanus. If the ends of a musculus fiber are held so that its length is abiding during such stimulation, the fiber generates a steady maximum force T ₀ – the plateau forcefulness of an isometric tetanus.

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Structure and Functions of Aquaporin-4-Based Orthogonal Arrays of Particles

Hartwig Wolburg , ... Andreas F. Mack , in International Review of Cell and Molecular Biology, 2011

3 OAPs and AQP4 in Cells Outside the Fundamental Nervous Arrangement

In skeletal musculus cells , OAPs were commencement detected by Rash and Ellisman (1974). In the sarcolemma of rat diaphragm myofibers, the authors determined the number and distribution of OAPs in the membrane area immediately surrounding a neuromuscular endplate. In the subjunctional membrane, OAPs were not establish, but with increasing distance from the junction, the density of OAPs increased to more than 50   μm^{−   2}. Nonetheless, the absenteeism of OAPs in the subjunctional membrane does not appear to be a full general feature of skeletal muscle cells. In the frog sartorius muscle, Heuser et al. (1974) found OAPs in muscle membranes beneath nerve terminals. Ellisman et al. (1976) compared fast and slow twitch muscle fibers of the rat and found a higher OAP density in the fast extensor digitorum longus (EDL) muscle than in the slow soleus musculus. The observation that after reinnervation of the slow soleus muscle by the nervus from the fast EDL muscle, the OAP density in the soleus musculus increases to values typical for the EDL muscle, suggested that the OAP density in the sarcolemma is neuronally regulated (Ellisman et al., 1978). However, simple denervation does non induce the disappearance of OAPs (Sirken and Fischbeck, 1985; Tachikawa and Clementi, 1979). Moreover, the subtract of OAP density in Duchenne dystrophy suggested a certain independence of the expression of OAPs from neuronal influences (Schotland et al., 1977, 1981; Wakayama et al., 1984). The aforementioned principle was described for the Fukuyama-type congenital muscular dystrophy (Wakayama et al., 1985, 1986), the 10 chromosome-linked muscular dystrophy (Shibuya and Wakayama, 1991), and the murine muscular dystrophy (Ellisman, 1981).

Frigeri et al. (1995) were the first to correlate the OAPs with the MIWC, which afterward was identified as the h2o channel protein AQP4 (Frigeri et al., 1998). In skeletal muscle cells, Shibuya et al. (2006) identified the OAP structure with AQP4 by using anti-AQP4 labeling of freeze-fracture replicas. The decrease of OAPs in muscle diseases every bit cited above, and recently summarized by Wakayama (2010), was correlated with a reduction of AQP4 on the protein level in muscle diseases including human Duchenne musculus dystrophy (DMD) and mdx mice, the beast model of DMD (Assereto et al., 2008; Au et al., 2008; Frigeri et al., 2001, 2002; Shibuya et al., 1997; Wakayama et al., 2002). However, whereas in DMD, the reduction of AQP4 poly peptide synthesis was due to decreased AQP4 transcription (Au et al., 2008; Wakayama et al., 2002), the situation in mdx mice seemed to exist different: Frigeri et al. (2001) observed a normal level of AQP4 mRNA with reduced amount of AQP4 protein, suggesting that the level of protein synthesis was downregulated independently of the charge per unit of transcription.

In the urinary system, Humbert et al. (1975) and Orci et al. (1981) described OAPs in membranes of light (principal) cells of the rat kidney collecting tubules. OAPs were observed only in lateral and basal membranes of these cells. Brown and Orci (1988) reported on a higher density in basal in comparison to lateral membranes. Searching for a possible office of OAPs in chief cells of the kidney collecting tubules, Nakamura and Nagano (1985) observed kidney cells of Brattleboro rats by means of freeze-fracturing. Brattleboro rats are vasopressin-deficient mutants, suffering from diabetes insipidus. The authors reported on an augmentation of OAP number in dehydrated rats and a diminution of OAP number in Brattleboro rats and concluded some part in water transport from the light cell to the basolateral extracellular space. Remarkably, the authors did this parallel to the discovery of aquaporins. However, at that place were contradictory results regarding the kinetics of OAP germination resulting in stabilization or destabilization depending on different time lengths of vasopressin treatment (Silberstein et al., 2004). This may be explained as the result of complex signaling processes from the vasopressin receptor-binding downstream to the factor expression of various AQP4 splice variants (Van Hoek et al., 2009). However, the primary water channel regulated past vasopressin in the kidney is AQP2 (Nielsen et al., 2002). In the basolateral membranes of cells in the distal segment of the lamprey kidney, Hatae (1983) described OAPs which were essentially larger (10,000–40,000   nm²) than those in mammalian tissues (400–1300   nm²: Neuhaus, 1990). Since the M23 isoform of AQP4 develops such huge lattices after transfection in AQP4-deficient cells (Furman et al., 2003), it would be interesting whether or not these isoforms exist in the lamprey kidney. In whatsoever case, water send in the kidney is not at all regulated by AQP4 lonely, including its isoforms, just by other aquaporins as well (Nielsen et al., 2002).

In lateral membranes of tracheal epithelium cells of the republic of guinea squealer, Inoue and Hogg (1977) described OAPs. Carson et al. (1984) and Gordon (1985) studied OAPs in bronchiolar epithelial Clara cells of the gilt hamster. In a number of different species, Bartels and Miragall (1986) described OAPs in basal membranes of pneumocytes. In dissimilarity, in the comprehensive review on aquaporins, King et al. (2004) described pneumocytes of both types equally AQP4-negative. Instead, Verkman (2007) claimed that pneumocyte type I independent AQP5 and the blazon Ii AQP3. However, we observed alveolar jail cell type I, but not Ii, expressing both AQP4 and OAPs (Fig. ane.threeA–C). The expression of AQP4 was substantially enhanced in nonsmall cell lung cancer cells by in-parallel disappearance of OAPs, suggesting an occurrence of AQP4 likewise in nonarray class nether pathological weather (Warth and Wolburg, unpublished; Fig. 1.3D–F). In cultured airway epithelial cells, Friend (1987) found an irreversible loss of OAPs and concomitantly, an endocytic internalization of OAP-positive membranes. In this case, AQP4 expression is well known from these airway epithelial cells (Nielsen et al., 1997; Verkman, 2007).

Effigy i.3. (A) Anti-AQP4 immunohistochemistry of normal lung tissue. The h2o channel poly peptide AQP4 is expressed frequently in alveolar cells. (D) shows a potent anti-AQP4 immunoreactivity in an adenocarcinoma of the aforementioned patient. (B), (C), (E), and (F) prove freeze-fracture replicas of the aforementioned case. (B) and (C) show membranes of an alveolar cell blazon I of normal lung tissue. (C) is a detail out of (B) illustrating many orthogonal arrays of particles (OAPs). (Due east) and (F) show membranes of the adenocarcinoma cell membranes of the aforementioned patient, as shown in (D). (F) is a particular out of (E), clearly illustrating that in these membranes, no OAPs are present, although the membranes are strongly immunopositive for AQP4. From a collaboration with Dr. Arne Warth (Institute of Pathology, Academy of Heidelberg, Frg).

In rat ciliary epithelium, Hirsch et al. (1988) found OAPs in nonpigmented cells. The comparison of membrane areas in contact and not in contact with the basal lamina showed that OAPs are equally distributed in both membrane domains. This is in obvious contrast to other cells, start of all astrocytes, where a strict correlation of OAP density with the attachment to the basal lamina exists (see below). In whatsoever instance, AQP4 expression has been detected in ciliary epithelium (Levin and Verkman, 2006), but to a lower degree than AQP1 (Hamann et al., 1998).

Other epithelia known to carry OAPs are the intestinal cells in the rat (Staehelin, 1972), and the rat gastric parietal cell (Bordi and Perrelet, 1978, Bordi et al., 1986). In intestinal epithelial cells of the mouse, we observed a strong AQP4-positive immunoreactivity (Fig. 1.4A), merely simply extremely few OAPs (Fig. one.4B), demonstrating that AQP4 can occur in a non-OAP configuration even under physiological conditions. Parietal cells of the stomach and deep catacomb epithelium of the ileum have been found to limited AQP4 (Koyama et al., 1999; Ma and Verkman, 1999). Carmosino et al. (2001) reported on OAP rearrangements in cultured parietal cells as a response to histamine treatment. Concomitantly with a decrease of water permeability, histamine treatment results in an internalization of AQP4, followed by a phosphorylation of AQP4 (Carmosino et al., 2007).

Effigy 1.4. (A) Immunohistochemistry of the epithelium in the jejunum of the mouse stained with an antibody against AQP4. (B) Freeze-fracture replica of the jejunum of the mouse showing but few orthogonal arrays of particles (OAPs; circled). The obvious discrepancy betwixt the stiff anti-AQP4 immunoreactivity and the low OAP density speaks in favor of the supposition that in this organ, AQP4 may occur mainly in the non-OAP configuration. (C) Immunohistochemistry of the olfactory epithelium of the rat stained with antibodies against AQP4 (in ruby) and the tight junction associated poly peptide ZO-1 (in green). Both the olfactory epithelium (OE) and the Bowman's gland cells (BG) are strongly immunopositive for AQP4. (D) Freeze-fracture replica of the olfactory epithelial cells of the rat showing only few OAPs, over again suggesting that AQP4 occurs in a non-OAP configuration.

In addition, even enteric neurons take been described to express AQP4 (Thi et al., 2008); yet, OAPs were not shown to be formed in these cells then far. In dissimilarity, OAPs were shown in sensory neurons of the olfactory system both of the tiger salamander (Miragall, 1983) and the newt (Usukura and Yamada, 1978), every bit well every bit in the rat vomeronasal sensory neuron (Miragall, 1983). In the olfactory epithelium of the rat, a strong anti-AQP4 staining of basal and supporting cells has been described, together with the secretory acinar and duct cells of the Bowman'south glands (Ablimit et al., 2006; Wolburg et al., 2008; Fig. 1.ivC). These cells were also positive for OAPs (Wolburg et al., 2008; Fig. ane.4D). The satellite cells of sensory and sympathetic ganglia (Elfvin and Forsman, 1978; Gotow et al., 1985; Pannese et al., 1977), and the supporting cells of the guinea grunter vestibular sensory epithelium (Saito, 1988), were investigated, in the preaquaporin period, for the occurrence of OAPs. Since in the meantime it had been published that the AQP4-knockout mouse suffered from impaired hearing (Li and Verkman, 2001), and age-related changes of AQP4 expression went along with age-related hearing loss (Christensen et al., 2009), nosotros compared the occurrence of AQP4 and OAPs in the organ of Corti of the rat. Nosotros establish an identical localization of AQP4 and OAPs in the supporting cells of the cochlear duct. The medial part of the cochlear duct including the screw limbus and the inner sulcus was immunoreactive for AQP4. In detail, medial interdental cells showed AQP4 labeling likewise as the basal portion of inner sulcus cells. In the lateral role of the cochlear duct including the outer sulcus and the screw ligament, Hensen cells showed very strong basolateral AQP4 labeling. Claudius cells exhibited basal AQP4-staining besides as outer sulcus cells with root processes protruding into the screw ligament (Hirt et al., 2010; Lopez et al., 2007). It is highly impressive how the expression patterns of AQP4 and of other aquaporins are finely balanced in lodge to regulate the water shunt between the perilymphatic and the endolymphatic spaces in the organ of Corti (Beitz et al., 1999; Hirt et al., 2010; Ishiyama et al., 2010).

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Myogenesis

Vittorio Sartorelli , Aster H. Juan , in Current Topics in Developmental Biological science, 2011

4.nine Conveying signals to the nucleus by the MAPK p38

In skeletal muscle cells, extracellular cues mediated by morphogen gradients, ligand–receptor, and soluble growth gene–receptor interactions are decoded and ultimately conveyed to the genome by chromatin-modifying complexes to regulate transcriptional output (reviewed in Guasconi and Puri, 2009). Protein modifications mediated by kinases and phosphates rapidly and effectively mediate cellular responses to environmental signals and internal processes past regulating protein interactions, enzymes activity, and protein localization (Pawson, 2007).

Within this context, signaling mediated by the MAPK p38 has received a cracking deal of experimental attention. The important office exerted by p38a in regulating the satellite quiescent state (Jones et al., 2005) is evidenced past the assay of p38a mutant mice, which shows delayed-cell-cycle get out and altered expression of cell bike regulators in cultured myoblasts (Perdiguero et al., 2007). Activation of p38, initiated past the transmembrane Ig-fibronectin—type III repeat CDO poly peptide—promotes formation of MyoD-E47 dimers, which in turn activate CDO transcription (Cole et al., 2004; Takaesu et al., 2006). E47 is a direct target of p38-mediated phosphorylation promoting MyoD-E47 heterodimer formation (Lluis et al., 2005). Different members of the MAPK p38 family exert opposing effects on musculus gene expression. While p38a/b favor muscle transcription by promoting MyoD-E47 heterodimer formation (Lluis et al., 2005) and MEF2D binding (Penn et al., 2004), engagement of the SWI/SNF chromatin remodeling complex via phosphorylation of the BAF60c subunit (Simone et al., 2004), and recruitment of the Ash2L-containing MLL protein circuitous through MEF2D phosphorylation (Rampalli et al., 2007), p38g antagonizes musculus factor expression past promoting recruitment of the H3K9 methyltransferase Suv39h1/KMT1 at the myogenin promoter through direct phosphorylation of Ser199 and Ser200 of MyoD (Gillespie et al., 2009).

An unexpected part of p38a in linking tumor necrosis gene (TNF) signaling to PcG proteins during muscle regeneration has been recently uncovered. Inflammatory cells populating sites of damaged muscles are an essential component of the regenerative phase, characterized past SC expansion and differentiation. Locally released cytokines, including interleukin 1,four,vi, and TNFa promote muscle regeneration (Charge and Rudnicki, 2004; Dhawan and Rando, 2005; Horsley et al., 2003; Serrano et al., 2008). TNFa regulates musculus regeneration by activating MAPK p38 (Chen et al., 2007). In proliferating, undifferentiated musculus cells, where p38a signaling is ineffective (Wu et al., 2000), the PRC2 complex prevents unscheduled gene expression by repressing transcription of muscle-specific myosins and musculus creatine kinase genes (Caretti et al., 2004). When proliferating SCs undergo differentiation, PRC2 is released from muscle structural genes—where is replaced past an activation complex (Caretti et al., 2004)—and relocated to Pax7 regulatory regions to repress gene expression (Palacios et al., 2010). Such PRC2 redistribution from musculus structural genes to Pax7 is regulated by p38a, which straight phosphorylates the human PRC2 catalytic subunit Ezh2 at Thr372 (corresponding to mouse Ezh2 Thr367), influencing recruitment of the Polycomb-related transcriptional repressor YY1 (Palacios et al., 2010). Indeed, p38a, Ezh2, YY1, and H3K27me3 are codetected at the Pax7 regulatory regions of differentiating primary myoblasts. Genetically or pharmacologically interfering with p38 or PRC2, results in connected Pax7 expression and expansion of SCs, which retain their ability to differentiate one time p38 or PRC2 blockade is removed (Palacios et al., 2010). While chromatin engagement of MAPKs p38 has been previously documented (Chow and Davis, 2006; de Nadal and Posas, 2010; Pokholok et al., 2006), the contribution of p38α to redistribute PcG proteins at specific genomic loci in response to inflammatory signals introduces an additional layer of regulatory refinement.

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Inflammatory Diseases of Muscle and Other Myopathies

Kanneboyina Nagaraju , ... Ingrid E. Lundberg , in Kelley and Firestein's Textbook of Rheumatology (Tenth Edition), 2017

Grade I Major Histocompatibility Complex Expression

Normal skeletal musculus cells do not constitutively express or brandish class I MHC molecules, although they can be induced to do and then by pro-inflammatory cytokines such as IFN-γ or TNF ^122,129-131 or by the alarmin HMGB1. ¹⁵² In dissimilarity, in homo IIMs, the early and widespread appearance of class I MHC in non-necrotic musculus cells is a striking feature, even in musculus cells distant from the lymphocytic infiltration. ^122,123,132 Class I MHC staining is usually observed on the sarcolemma of muscle fibers, but some fibers too show staining in both the sarcolemma and the sarcoplasm (see Effigy 85-3A and B). In some patients, the expression is restricted to a few clusters (oft early in the disease), whereas in others, near every fiber is positively stained, particularly in belatedly-stage and treatment-resistant cases. Researchers have explored the biologic significance of these observations past generating a conditional transgenic mouse model overexpressing syngeneic mouse class I MHC. The overexpression of form I MHC molecules in the skeletal musculus of mice results in the evolution of clinical, biochemical, histologic, and immunologic features that resemble homo myositis and provides a close model of the human being disease. The disease in these mice is inflammatory, express to skeletal muscle, cocky-sustaining, more severe in females, and often accompanied by MSAs. ¹³³ Recent studies in this model farther suggest that grade I MHC overexpression leads to endoplasmic reticulum (ER) stress, muscle atrophy, and a decrease in the force generation capacity of skeletal musculus, suggesting a function for grade I MHC musculus weakness in myositis. ^134,135

A number of observations in man myositis patients and in the mouse model of myositis suggest that form I MHC molecules mediate muscle fiber harm and dysfunction in the absence of lymphocytes. For example, in human being myositis, the induction of course I MHC antigen in muscle fibers occurs early on, preceding inflammatory cell infiltration. ^136,137 Grade I MHC staining of human myositis biopsies shows both a cell surface and a sarcoplasmic reticulum pattern of internal reactivity, demonstrating that some of the grade I MHC molecules may be retained in the ER of these fibers. ^83,123,138 Persistent grade I MHC overexpression in muscle fibers tin can exist in the absenteeism of an inflammatory infiltrate. ¹²⁸ The controlled induction of form I MHC in the mouse model is followed by muscle weakness before mononuclear cell infiltration. ¹³³ Researchers have recently shown that in vivo gene transfer of class I MHC plasmids attenuates muscle regeneration and differentiation. ¹³⁹ Together, these observations, and particularly the obvious retention of grade I MHC within the prison cell in both human and murine disease, indicate that the muscle fiber damage seen in myositis may not exist solely mediated past immune attack (e.thou., CTLs, autoantibodies) merely may likewise be mediated through nonimmunologic mechanisms such every bit the ER stress response and hypoxia. Activation of ER stress in cells is linked to the induction of unlike forms of cell death such as autophagy and apoptosis. The expression of molecules that facilitate autophagy (tumor necrosis factor-related apoptosis-inducing ligand [TRAIL]) and apoptosis (TNF-like weak inducer of apoptosis [TWEAK]) were increased in myositis patients, providing a molecular ground for progressive muscle damage in myositis. ^140,141

In myositis, it appears that overexpression of course I MHC in myofibers initiates a series of jail cell-democratic changes that contribute to myofiber pathology. Recent investigations have indicated that overexpression of class I MHC on muscle fibers results in the activation of the NF-κB and ER stress response pathways in human inflammatory myopathies and in the mouse model of myositis. ^83,142 NF-κB can be activated within minutes by a multifariousness of stimuli, including inflammatory cytokines such every bit TNF and IL-one, T cell activation signals, and stress inducers. It is probable that in homo myositis, NF-κB activates both archetype (pro-inflammatory cytokines) and nonclassic (ER stress response) pathways. ^83,142-145 Furthermore, there is testify that downstream target genes (east.m., class I MHC, intercellular adhesion molecule [ICAM], monocyte chemoattractant protein [MCP]-1) regulated by the NF-κB pathway are highly upregulated in myositis patients. ^138,146,147 Contempo studies have indicated that NF-κB p65 is activated both in human myositis biopsies and in the mouse model, ^{83,142,148,149} suggesting that this pathway may be directly involved in muscle cobweb damage (Figure 85-4).

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