Ординатура / Офтальмология / Английские материалы / Ocular Periphery and Disorders_Dartt, Bex, Amore_2011

BA1

Figure 9 Lateral view of a 3.5-day chick embryo showing the sites of expression of the MyoR gene. Note the finger-like projections (arrows) extending dorsal and caudal to the optic vesicle, along the sites at which the dorsal and ventral oblique are expanding.

locations. Subsequently, crest cells close behind each of these muscle primordia, creating the appearance of an island of myoblasts/myofibers amid a sea of crest cells. How these focal distortions are established is unknown. The cell surface adhesion molecule semaphorin 3A is expressed by mesodermal cells in these projections, but its role in not known.

Summary

The early stages of extraocular muscle formation are well described but poorly understood mechanistically. They arise at discrete sites within unsegmented head paraxial mesoderm then launch into developmental programs that share some features with trunk and branchial muscles but are largely and surprisingly unique. Passive distortions of the mesoderm-neural crest interface bring these muscle primordia to their definitive locations around the ocular

globe, where they become surrounded then infused by connective-tissue forming neural crest cells, which largely direct both the gross and microscopic differentiation of these muscles.

See also: Extraocular Muscles: Extraocular Muscle Anatomy.

Further Reading

Borue, X. and Noden, D. M. (2004). Normal and aberrant craniofacial myogenesis by grafted trunk somitic and segmental plate mesoderm. Development 131: 3967–3980.

Bryson-Richardson, R. J. and Currie, P. D. (2008). The genetics of vertebrate myogenesis. Nature Reviews Genetics 9: 632–646.

Evans, D. J. R. and Noden, D. M. (2006). Spatial relations between avian craniofacial neural crest and paraxial mesoderm cells.

Developmental Dynamics 235: 1310–1325.

Grenier, J., Teillet, M. A., Grifone, R., Kelly, R. G., and Duprez, D. (2009). Relationship between neural crest cells and cranial mesoderm during head muscle development. PLoS ONE 4: e4381.

Marcucio, R. M. and Noden, D. M. (1999). Myotube heterogeneity in developing chick craniofacial skeletal muscles. Developmental Dynamics 214: 178–194.

Noden, D. M. and Francis-West, P. (2006). The differentiation and morphogenesis of craniofacial muscles. Developmental Dynamics 235: 1194–1218.

Noden, D. M., Marcucio, R. M., Borycki, A-G., and Emerson, C. P., Jr. (1999). Differentiation of avian craniofacial muscles. I. Patterns of early regulatory gene expression and myosin heavy chain synthesis.

Developmental Dynamics 216: 96–112.

Noden, D. M. and Schneider, R. A. (2006). Neural crest cells and the community of plan for craniofacial development: Historical debates and current perspectives. In: Saint-Jeannet, J. P. (ed.) Neural Crest Induction and Differentiation, pp. 1–23. Boston, MA: Landes Bioscience and Springer Science Media.

Tzahor, E. (2009). Heart and craniofacial muscle development: A new developmental theme of distinct myogenic fields. Developmental Biology 327: 273–276.

Yoshida, T., Vivatbutsiri, P., Morriss-Kay, G., Saga, Y., and Iseki, S. (2008). Cell lineage in mammalian craniofacial mesenchyme.

Mechanisms of Development 125: 797–808.

Glossary

Abducens nerve (CNVI) – The cranial motor nerve which controls contraction of the lateral rectus muscle.

Aponeurosis – A large flat and dense connective tissue layer which anchors a muscle to its origin or insertion.

Excyclotorsion – An outward rotation of the upper pole of the vertical midpoint of each eye. Incyclotorsion – An inward rotation of the upper pole of the vertical midpoint of each eye.

Myosin heavy chain (MyHC) isoforms – The major contractile protein in muscle is myosin, which in turn is composed of two heavy and four light chains.

MyHC isoforms are responsible for the shortening velocity of muscle fibers during muscle contraction.

Oculomotor nerve (CNIII) – The cranial motor nerve which controls contraction of the levator palpebrae superioris muscle, the inferior, medial, and superior rectus muscles, as well as the inferior oblique muscle. It also contains parasympathetic preganglionic axons that are destined for the ciliary body and iris sphincter muscles of the eye.

Ora serrata – The junction between the neurosensory retina and the ciliary body.

Satellite cells – Myogenic precursor cells that reside between the sarcolemma of the muscle fiber and its surrounding basal lamina. They are responsible for myofiber repair and regeneration after injury or in disease.

Strabismus – A disorder characterized by altered tonus or restrictive disease of the extraocular muscles resulting in loss of conjugate binocular vision.

Trochlear nerve (CNIV) – The cranial motor nerve which controls contraction of the superior oblique muscle.

The extraocular muscles (EOMs) have an extremely complex anatomy, both at the gross anatomical and histological levels. The main function of the EOM is to move the eyes in the orbit such that the eyes can be precisely positioned to allow focusing of the visual world on corresponding regions of each retina. Within each bony orbit the EOM includes four rectus muscles (superior,

lateral, inferior, and medial) and two oblique muscles (superior and inferior; Figure 1). A seventh skeletal muscle within the human orbit is the levator palpebrae superioris (LPS) muscle. It is the superior-most muscle in the orbit directly inferior to the frontal bone forming the orbital roof. The levator lies directly inferior to the periorbita and inserts via a large aponeurosis into the eyelid skin. The descriptions of the EOM will be primarily based on human muscles for ease of presentation. The general characteristics of size, shape, fiber type, and the like are similar for all EOM in principle, although they vary in detail for each specific animal that has been examined.

Gross Anatomy of the EOM within the Orbit

The four rectus muscles originate from the apex of the bony orbit by a common tendinous annulus (of Zinn). The tendinous annulus attaches to the greater and lesser wings of the sphenoid bone as well as to the periosteum, the dense connective tissue lining the orbit. The annulus crosses over the inferior portion of the superior orbital fissure and runs superior and medial to the optic foramen (Figure 2). The superior (Figure 3) and medial rectus muscles arise from the superior part of this annulus, while the inferior and lateral rectus muscles arise from its inferior part. These muscles are all surrounded by a connective tissue capsule called Tenon’s capsule and are described as forming the muscle cone. The superior oblique (SO) muscle originates from the periosteum slightly superior and medial to the tendinous annulus. The inferior oblique (IO) muscle is the only EOM that does not arise from the orbital apex, but rather originates from the lateral border of the lacrimal fossa, which is anterior and nasal within the orbit.

The rectus muscles run anteriorly to insert on the sclera on the anterior pole of the globe, at a location superficial to the ora serrata. The lateral and medial rectus muscles in human adults are approximately 41 mm in length. The superior rectus (SR) is the longest, averaging 42 mm, while the inferior rectus is the shortest averaging 40 mm. The insertions of the muscles onto the globe vary in their distance from the corneal limbus, with the SR furthest and the medial rectus closest. According to a study by Fuchs in 1884 on cadaver eyes, the distance from the limbus of rectus muscle insertions onto the globe

Superior

Medial

Figure 2 Bony orbit with the tendinous annulus indicated in the orbital apex by the black oval. It encloses the optic foramen superiorly and crosses the inferior portion of the superior orbital fissure.

decreases as one progresses sequentially in the following order: SR at 7.7 mm, lateral rectus at 6.9 mm, inferior rectus at 6.5 mm, and medial rectus at 5.5 mm. However, when measured in vivo during strabismus surgery the distances were shorter for all muscles: SR at 6.7 mm, lateral rectus at 6.2 mm, inferior rectus at 5.89 mm, and medial rectus at 4.5 mm. The insertions typically are circumferential to the limbus. However, wide variations in obliquity and regularity of the insertions are common, both from patient to patient and from muscle to muscle, even in the same eye. These differences are important in the context of planning surgery on the EOM for treatment of eye motility disorders, such as strabismus. Recent studies convincingly show that the distance from muscle

Figure 3 Dissection of the human orbit from the superior view with the orbital bony roof and the periorbita removed. The most superficial structure is the frontal nerve. Directly inferior to the frontal nerve is the levator palpebrae superioris (LPS, elevated by scissor tips). Inferior to the LPS is the superior rectus muscle.

insertion to the limbus has a high inter-individual variability, and there appears to be no correlation between insertional distance and the amount of deviation in strabismus patients.

The lateral rectus is innervated by the abducens nerve (CNVI) on its intraconal or deep surface (Figure 4). The SR muscle is innervated on its intraconal surface by the superior division of the oculomotor nerve (CNIII), while the inferior and medial rectus muscles and the IO muscles

Figure 4 Dissection of the human orbit from the superior view. The bony roof, periorbita, levator palpebrae superioris, and superior rectus muscles are removed. The abducens nerve can be traced from where it pieces the dura in the posterior cranial fossa, through the superior orbital fissure, which has been opened in this dissection, to where it enters the lateral rectus muscle which it innervates.

are innervated by the inferior division of CNIII (Figure 5). All the cranial motor nerves except for the trochlear nerve (CNIV) enter the muscles intraconally, and all the motor nerves enter at approximately one-third of the muscle’s length from the orbital apex (Figure 6). The six EOMs control the position of the eye in the orbit while orbital fat and fascia constrain the paths of the muscles within the orbit.

The two horizontal rectus muscles of each eye are agonist–antagonist pairs with relatively straightforward function; the medial rectus adducts the eye and the lateral rectus abducts it (Figure 7). By contrast, the SO and the IO muscles and the two vertical rectus muscles have far more complex functions. The primary direction of movement caused by the superior and inferior rectus muscles is elevation and depression, respectively. However, due to the shape of the bony orbit and their sites of origin and insertion, the vertical recti have secondary and tertiary actions that are torsional and horizontal, respectively. The SR, for example, is a secondary incyclorotator, moving

Figure 5 Deep orbital dissection from the superior view. The levator palpebrae superioris and superior rectus muscles are reflected medially to allow visualization of the superior and inferior divisions of the oculomotor nerve (CNIII).

the superior pole of the eye toward the nose; its tertiary function is adduction. The inferior rectus muscle, by contrast, is also a secondary excyclorotator, but similar to the SR is a tertiary adductor (Figure 8). Thus, the SR, if acting unopposed, would elevate, adduct and incyclotort the eye such that the eye would be looking up and in. The inferior rectus, if acting unopposed, would depress, adduct, and excyclotort the eye such that the eye would be looking down and in. The superior and IO muscles have a similarly complex cyclovertical functions. The primary action of these two muscles is rotation or torsion, but due to the angle which they take in the orbit toward their insertion on the sclera, they will also elevate (IO) or depress (SO) the eye; both abduct the eye. The remarkable balance and integrity of the ocular motor plant becomes evident when one considers that to look straight superiorly without moving the head, both the IO (a primary excyclorotator, secondary elevator, and tertiary abductor) and the SR (a primary elevator, secondary incyclorotator, and tertiary adductor) coordinately contract. The same is true for the inferior rectus and SO muscles moving the eye straight inferiorly.

The SO muscle is the thinnest, roundest, and longest of the EOM. The muscle runs 32 mm along the border of the medial wall and roof of the orbit, and 10–15 mm from the orbital margin it becomes tendinous and passes through

Figure 7 The lateral rectus (LR) and medial rectus (MR) muscles move the eyes in the horizontal plane. The MR adducts the eye, moving the eye toward the midline. The LR abducts the eye, moving the eye away from the midline. These muscles are antagonists; they have opposite functions.

Figure 9 The superior oblique muscle can be seen along the medial wall of the orbit. The trochlear nerve (CNIV) is seen coursing along the muscle’s superior surface and enters into the posterior 1/3 of the muscle on its medial side.

a fibro-fascial structure called the trochlea, located anteriomedially under the orbital roof. The trochlea changes the orientation of the muscle, becoming the functional origin of this muscle. The tendon of the SO courses deep to the SR muscle to insert into the sclera laterally on the posterior pole of the globe. The position of the SO tendon insertion, posterior and temporal to the center of rotation of the globe, explains the complex cyclovertical function

of the muscle. The trochlear nerve (CNIV) innervates this muscle, coursing first on the muscle’s superior side, and finally entering the muscle superiomedially at about the proximal one-third of the muscle’s length (Figure 9).

The IO muscle is approximately 37 mm in length and travels in a similar orientation to the reflected tendon of the SO distal to the trochlea. The muscle runs inferior to

the inferior rectus muscle and inserts into the sclera of the posterior pole on the lateral side of globe. The insertion is relatively close to the macula of the retina. The IO is innervated by the inferior division of the oculomotor nerve (CNIII) on its superior surface with the nerves entering the muscle at approximately the posterior one-third.

Histological Anatomy of the EOMs

Overall Organization

The EOMs have a complex anatomical organization at the microscopic level. These muscles differ from those in the limbs and body in that the muscle fibers themselves have extremely small cross-sectional areas, with an average in human EOM of 340 200 mm2 (Figure 10). In addition, there is a great deal of variability in the myofiber crosssectional areas; this heterogeneity is quite striking. In cross-section, two distinct layers can be seen in all six EOMs, the orbital and the global layers. The orbital layer faces the bony orbit and is composed of myofibers with extremely small cross-sectional areas, with a mean of

Orbital

Global

Figure 10 A cross section of the medial rectus muscle from a Rhesus monkey immunostained for the presence of the fast myosin heavy chain (MyHC) isoform, which labels all forms of the fast MyHC. The orbital layer is composed of myofibers with extremely small cross-sectional areas, while myofibers in the global layer are somewhat larger. Bar is 50 mm.

260 160 mm2. The global layer faces the globe, and the myofibers are markedly bigger than those in the orbital layer with a mean of 440 200 mm2. However, they are still very small compared to body and limb skeletal muscle myofibers, which typically range from 3500 to 4000 mm2 in the human soleus muscle, as an example.

The total number of myofibers found within each of the six EOMs varies significantly. When measured in the mid-belly region of the muscles, the numbers of myofibers in the orbital layer in human EOM range from 7400 to 14 600 and in the global layer the numbers range from 8000 to 16 400 myofibers. This variation in myofiber number is seen in other species where the fiber number has been examined, although the range varies significantly from human. For example, monkey EOMs have approximately half the number of myofibers compared to human EOM. In addition, total myofiber number decreases along the length of each muscle as the insertions are approached. This variation in fiber number is due to the fact that the majority of myofibers within the EOM does not run tendon to tendon, as has been shown by a number of investigators. This can be demonstrated quite easily by serially sectioning muscles and following individual myofibers in consecutive sections (Figure 11). This is also supported by electrophysiological evidence demonstrating that the force produced by stimulating two separate motor unit groups individually is often more than the force produced by stimulating both motor groups simultaneously. This nonlinearity, or loss of force in summated motor units, is postulated to be caused by the lateral dissipation of force due to myofibers that do not reach the tendon ends.

Innervation

Most skeletal muscles receive their motor nerve innervation in approximately the middle, and the neuromuscular junctions form a single endplate zone. Neuromuscular junctions are a pentomer composed of four distinct subunits: a (2), b, g, and d. During maturation, the g subunit is replaced with an e subunit, forming the adult acetylcholine receptor. In contrast to limb skeletal muscle, the EOM maintains a subpopulation of neuromuscular junctions with the immature subunit configuration.

While the vast majority of EOM muscle fibers is fasttwitch fibers and receive a typical en plaque type of neuromuscular junction somewhere along their length, the EOM also contains two types of multiply innervated myofibers. These account for approximately 10% of the fibers in the global and orbital layers. In the global layer, these multiply innervated myofibers contain slow-tonic myosin and appear to be innervated by small en grappe endplates along their length. These en grappe neuromuscular junctions retain the g subunit of the acetylcholine receptor, rather

than the e subunit of the mature neuromuscular junction. There are reports in the literature that the en plaque endings in mammalian EOM can also express the immature g subunit of the acetylcholine receptor. This type of multiply innervated myofiber develops a slow-graded or tonic tension when the nerves are stimulated. The orbital layer has a second type of multiply innervated myofiber. These fibers have a neuromuscular junction in the central one-third of their length with typical en plaque structure. In addition, however, there are multiple en grappe endings at the myofiber ends. Thus, the central region displays fast-twitch properties with nerve stimulation while the fiber ends display slow-tonic contractile properties.

As a result of fibers that do not run the origin-to- insertion length of the muscles and the presence of neuromuscular junctions on fiber ends, neuromuscular junctions are found throughout the length of the EOM. This has important implications for pharmacologic and surgical manipulations of the muscles in the treatment of eye motility disorders such as strabismus and nystagmus.

Skeletal Muscle Fiber Types

From a physiological perspective, the EOMs have extremely fast contractile properties, produce low levels of force, and are relatively fatigue resistant. These properties are conferred on muscle fibers by their expression of specific contractile proteins such as the myosin heavy chain isoforms (MyHC), as well as differences in cellular organelles such as mitochondria and other cellular metabolic pathways. One unusual aspect of EOM histology is the expression, within and between these two layers, of a complex pattern of MyHC expression.

Myosin Isoform Complexity in the EOM

Skeletal muscle fibers in body and limb muscles have generally been described as fast, expressing MyHC type IIa, IIb (nonhuman), and/or IIx/d, or slow, expressing MyHC type 1. However, this fiber type organization breaks down in the EOM, as was described by Mayr in 1971. On average, only 16% of the myofibers within the orbital layer are positive for the slow MyHC (MYH7), while 14% of the myofibers in the global layer are positive for slow MyHC. Thus, the vast majority of myofibers expresses the fast MyHC2a isoform (MYH2) which is responsible for the extremely fast contractile properties of the EOM. However, the EOMs express, in total, at least eight distinct MyHC isoforms: 2a, 2x/d, 1 (b-cardiac), developmental (embryonic), neonatal (perinatal), a- cardiac, slow-tonic, and EOM-specific. If serial sections of individual myofibers are examined immunohistochemically, it quickly becomes evident that single myofibers express more than one isoform (Figure 12). In the Kjellgren et al. study of adult human EOMs, single fibers immunostained for the slow or MyHC type 1 isoform can co-express either or both slow-tonic MyHC and a- cardiac MyHC. If just the slow myofibers are considered, they can express:

1.only MyHC type 1,

2.only slow-tonic,

3.only a-cardiac,

4.only EOM-specific,

5.MyHC type1 and slow-tonic,

6.MyHC type 1 and a-cardiac,

7.myosin type 1 and EOM-specific,

8.slow-tonic and a-cardiac,

9.slow-tonic and EOM-specific,

Fast myosin

Developmental myosin

Neonatal myosin

Figure 12 Three serially cut cross sections from a region of a rabbit lateral rectus muscle approaching the anterior 1/3 of the muscle. They have been immunostained for fast, developmental, and neonatal myosin heavy chain (MyHC) isoforms. One group of muscle fibers has been circled in yellow with two fibers identified by a light-green arrow and a fiber numbered 2. Note that the fiber indicated by the green arrow is positive for fast and neonatal MyHC but negative for developmental MyHC. Note that fiber 2 is negative for fast MyHC but positive for developmental and neonatal MyHC. A second group of muscle fibers has been circled in red with two fibers identified as fiber 3 and 4. Fiber 3 is positive for fast MyHC but negative for both developmental and neonatal MyHC, while fiber 4 is positive for all three of these isoforms. The fiber indicated by the large blue arrow is negative for fast MyHC, but positive for both developmental and neonatal MyHC.

10.a-cardiac and EOM-specific,

11.slow type 1, slow-tonic, and a-cardiac,

12.slow type 1, slow-tonic, and EOM-specific,

13.slow-tonic, a-cardiac, and EOM-specific, or

14.all four isoforms (Figure 13).

These combinations may result in 14 types of fibers. It is also known that embryonic (developmental) and neona- tal-specific MyHC isoforms are also expressed by some of these fibers as well. The same complexity is seen with the myofibers positive for the fast MYHC type 2A. Single fibers can also express one of one or more of these isoforms: developmental, neonatal, EOM-specific, and 2x/d. These types of myofibers are referred to as hybrid fibers, and they can be seen, albeit to a lesser extent, in other muscles such as the diaphragm. Even when only MyHC expression characteristics are considered, the high degree of individual myofiber polymorphism seen in the collective data from many laboratories strongly supports the view that there is a continuum of myofiber types within the EOM. In some ways, trying to fit the EOM into the classical fiber typing scheme is misleading, as it does not deal effectively with the hybrid and mismatched fibers.

This complexity has significant ramifications for muscle function. MyHC isoforms control muscle-shortening velocity, and it has been proposed that this type of polymorphism allows for fine-tuned control over a wide range of forces, velocities, and fatigue properties. From a teleological perspective, these coexpression patterns would allow the EOM to contract at high velocities but with minimal fatigue, a characteristic that is important for muscles that are continually functioning in order to maintain fixation of gaze on the fovea in an infinite number of eye positions. Additionally, studies have shown that the EOMs show rapid alterations in MyHC isoform expression in response to stretch, alterations in hormones, botulinum toxin treatment, denervation, and the like.

Nonuniform Expression of MyHC Isoforms along the Muscle Length

Immunohistological examination of cross-sections taken from the tendon ends and the middle region of an EOM shows that the overall percentages of specific MyHC isoforms change dramatically depending on the location along the muscle length (Figure 14). For example, in a study of rat EOM, within the orbital layer the mid-belly region expresses EOM-specific MyHC but this isoform is completely excluded from the tendon ends where the embryonic (developmental) MyHC isoform is present. This is seen even at the level of single isolated myofibers, where the fiber ends express neonatal MyHC and the mid-region of the same myofiber expresses fast MyHC. This type of non-uniform expression of MyHC along the length of single fibers also is seen in the intrafusal muscle

fibers found in muscle spindles, another specialized myofiber structure. Using single myofiber reconstructions to localize neonatal MyHC isoform expression in single fibers, myofibers are found that are neonatal MyHCpositive from fiber tip to fiber tip, but it is more common to find single myofibers with variable percentages of the total fiber length expressing this isoform, including fibers where the expression is discontinuous. It is emerging that these types of hybrid fibers are present in other craniofacial muscles, such as jaw and laryngeal muscles.

In limb and body skeletal muscles, innervation, neuromuscular activity, exercise (use/disuse), mechanical loading or unloading, hormones, and aging all cause adaptive changes in contractile properties and metabolic profiles. This supports the view that expression of contractile proteins within muscle fibers is extremely dynamic and possesses an incredible adaptability to meet the physiological demands placed upon them. EOMs are constantly active and appear to represent the far end of a continuum of skeletal muscle types relative to their ability to react and adapt to changing functional needs. As the MyHC controls shortening velocity, this MyHC polymorphism would result in a gradation of function within populations of single myofibers. In other words, a continuum of force and movement would be possible, as the contractile properties of each myofiber would reflect its particular subset of contractile proteins. An example of this is shown in Figure 15, where force was determined using a single fiber preparation and the MyHC content was analyzed for each single fiber using polyacrylamide gel separation. As can be seen, fibers that produce the same amount of force can have significantly different MyHC isoform expression patterns.

While it has not been demonstrated specifically within EOM myofibers, it is a well-known characteristic of multinucleated myofibers that each myonucleus controls

the expression of proteins in what is called its myonuclear domain. An elegant study by the Hardeman laboratory showed that transcription occurs in pulses within individual myonuclei, and the activities of single nuclei are not in sync with each other. Each nucleus, and thus each myonuclear domain, is individually controlled, and protein synthesis is a dynamic process that is altered at the local level to respond to the particular stress or strain.

The advantage conferred by this complexity within populations of individual EOM myofibers can be hypothesized as an adaptation to the functional needs of eye movements in maintaining binocular vision and highly coordinated vergence movements, where a continuum of contraction forces and speeds would be required. Functionally, the complex MyHC co-expression patterns, and their presumed continuous modulation, would allow finely tuned control over these movements, as the kinetics of the EOM would cover a wide range of eye positions and velocities.

Other Molecules Heterogeneously Expressed

The heterogeneity of individual myofibers is made even more complex not only by differences in other contractile proteins, such as myosin light chains and troponin, but also by other metabolic differences. Of the molecules that have been specifically examined, the EOM often has patterns of expression not seen in limb muscle. For example, myosinbinding protein C has three isoforms. Despite the fact that the vast majority of myofibers within human EOM is positive for fast MyHC, the EOM does not express the fast form of myosin-binding protein C. Recent work showed that, in contrast to limb skeletal muscles, high levels of glycolytic and oxidative pathways coexist within single myofibers in the EOM. This molecular mismatch would provide these very active muscles with both fatigue resistance and fast contractile properties.

Fiber 2

Fiber 1

Figure 15 Relative percentages of four myosin heavy chain isoforms from two single-skinned myofibers with the same shortening velocity of 9.4 fiber lengths per second as determined using single-skinned fiber physiology in the EOM of rabbits. Note that fiber 1 has three isoforms expressed, and it contains type IIX as its main isoform, while fiber 2 has only two isoforms expressed, and IIB is the isoform with the greatest amount of expression.

Continuous Remodeling in Normal

Adult EOM

Early studies by Moss and LeBlond demonstrated that the myonuclei within mature, multinucleated myofibers are postmitotic. However, muscle has regenerative capacity that resides in myogenic precursor cells called satellite cells, and these cells become activated, divide, and are responsible for muscle repair and/or regeneration of new fibers in disease and after injury. The EOM in normal adult mammals maintain an elevated number of satellite cells throughout life (Figure 16), which divide and integrate continuously into apparently normal muscle fibers. Concomitantly with nuclear addition, apoptosis of individual myonuclei is seen with apparent segmental cytoplasmic remodeling. The factors that control this process are unknown, but this process represents another dynamic