Introduction
The extraocular muscles (EOM) are a complex group of skeletal muscles located within the bony orbit. They function in a highly coordinated manner to perform conjugate eye movements, maintain primary gaze position, and provide visuomotor fusion—maintaining corresponding visual elements within the binocular field to fall on corresponding retinal loci. In addition, the eyes are able to follow moving objects, called smooth pursuit, and accomplish rapid changes in fixation, called saccades. This is accomplished by a very highly organized oculomotor control system in the brain, with the EOM forming the final effector tissues. Understanding how the EOM adapt to changing visual demands is critical to the development of improved treatment strategies to realign the eyes when the system fails, as in strabismus or nystagmus.
The EOM have many distinct and complex properties that distinguish them from noncranial skeletal muscles, many of which are normally associated with developing or regenerating muscle. This includes a population of multiply and polyneuronally innervated myofibers, retained expression of the immature subunit of the acetylcholine receptor, neural cell adhesion molecule, and “immature” myosin heavy chain isoforms. The EOM also have the capacity to remodel continuously throughout life. From a clinical perspective, the EOM have a distinct propensity for or sparing from a number of skeletal muscle diseases. EOM share some of their unusual characteristics with other craniofacial muscles, such as the laryngeal muscles, and the potential developmental basis for their unusual properties and disease profiles is presented.
The bony orbit
The eyes and other orbital contents are protected in deep bony orbits that are roughly pyramidal in shape ( Fig. 7.1 ). The orbit is largest just inside the orbital margin at its anterior extent and smallest at its posterior extent, the apex. The orbital margins are composed of the frontal bone superiorly, the zygomatic process of the frontal bone and the frontal process of the zygomatic bone laterally, the zygoma and the maxillary bone inferiorly, and the frontal process of the maxillary bone, the lacrimal bone and the maxillary process of the frontal bone medially ( Fig. 7.1 ). However, direct impact to the bony margin can result in fracture of the bones within the orbit (see Box 7.1 ). The bony orbit has a thick bony roof composed of frontal bone and a portion of the lesser wing of the sphenoid bone. The lateral wall is composed of the zygomatic bone and the greater wing of the sphenoid. The relatively thin floor is composed of the maxillary bone, a small and variable part of the palatine bone, and the zygomatic bone. The thin medial wall is composed of the maxillary, the lacrimal, ethmoid, and sphenoid bones, from anterior to posterior respectively. As a result of this bony configuration, the globe is relatively protected from injury caused by direct impacts to the face and orbital margins, particularly if there are no bony fractures.
Bony fractures of the thin orbital walls can occur with blunt impact to the orbital margins. The increased force causes the bone to “blowout” into the sinuses, with the inferior and medial walls most susceptible to fracture. Sometimes the EOM become entrapped at the fracture site, as evidenced by restricted movements in the range of function of the entrapped muscle. These must be surgically repaired.
An understanding of the geometry of the bony anatomy relative to maintenance of eye position is critically important. The medial walls are parallel to each other, while the plane of the lateral wall in each orbit is 45 degrees from the sagittal plane formed by the medial wall ( Figs. 7.1 and 7.2 ). Additionally, the geometry of the orbital bones requires that both globes need to be partially adducted in the primary position of gaze, which is looking directly straight ahead. Maintenance of eye position in primary gaze thus requires a constant steady-state level of tension in all the EOM, referred to as tonus.
The apex of the bony orbit has three major foramina: the optic foramen, and the superior and inferior orbital fissures. The nerves and blood vessels to the majority of structures within the orbit enter or exit through these foramina. A number of small foramina also open into the orbit, allowing entry and exit of nerves and vasculature to a wide array of structures in the orbit and head.
Extraocular muscle anatomy
There are six EOM in each orbit whose function is to move the eyes: four rectus muscles, superior, medial, inferior, and lateral; and two oblique muscles, inferior and superior ( Fig. 7.3 ). In addition there is a seventh skeletal muscle in each orbit, the levator palpebrae superioris, which inserts into the upper eyelid and functions in elevating the palpebral fissure. Although its cranial nerve innervation is similar to the EOM, functionally and metabolically it is distinct, and will not be discussed further in this chapter.
The four rectus muscles take their origin in part from the bones at the apex of the orbit, but also from a connective tissue ring called the tendinous annulus. They course anteriorly to insert into the sclera anterior to the equator of the globe, a key factor when considering their functional effects on eye movements. Classically, this insertion is described as directly external to the ora serrata; however, recent studies demonstrate that insertions of the rectus muscles range from 2.25-mm posterior to 2.25-mm anterior to the ora serrata, with 90% of the insertions within 1 mm. Generally considered to be tendinous at the insertion site into the globe, the medial and lateral rectus muscles in humans may contain myofibers that extend directly to the sclera, an important consideration for incisional strabismus surgery. The insertions of the four rectus muscles increase in distance from the corneal limbus circumferentially, with the medial rectus closest and the superior rectus furthest. The distances were originally determined on cadaveric material ; however, recent analyses on living adult patients during strabismus surgery show that the average distances from the corneal limbus to the rectus muscle insertions have large interindividual variations. In part, this explains the disparate measurements seen in the literature. One typical study measured the distances from the limbus to muscle insertion as 6.2 ± 0.6 mm for the medial rectus, 7.0 ± 0.6 mm for the inferior rectus, 7.7 ± 0.7 mm for the lateral rectus, and 8.5 ± 0.7 mm for the superior rectus. Distances can vary up to 4 mm, even between the same muscles in both eyes of one individual; these differences do not correlate with the primary position of the eye or surgical success for strabismus patients. Thus, there is a significant amount of variation in rectus muscle insertions, and this variability has important consequences for incisional surgery of the EOM.
The superior and inferior oblique muscles have distinct paths compared with the rectus muscles. The superior oblique takes its origin from the dense connective tissue periosteum lining the orbit just superior and medial to the attachment of the tendinous annulus, and courses anteriorly along the border between the orbital roof and the medial orbital wall. Approximately 10 to 15 mm posterior to the orbital margin it becomes tendinous and enters the trochlea, a cartilaginous and dense connective tissue structure attached to the orbital periosteum. Emerging from the trochlea, the superior oblique muscle passes posteriorly at a 51-degree angle to the axis of the eye in primary position and inserts into the sclera. The trochlea thus serves as the “de facto” origin, creating the vector of force that moves the globe. The insertion of the superior oblique is on the superior pole deep to the superior rectus muscle, but in contrast to the rectus muscles, inserts posterior to the equator of the globe ( Fig. 7.3 ). The inferior oblique muscle is the only EOM that does not take its origin from the apex of the orbit; instead, it originates from the anteromedial orbital floor ( Fig. 7.3 ). The inferior oblique muscle courses posteriorly and inferior to the inferior rectus and inserts into the sclera posterior to the equator of the globe, running in a parallel direction to the superior oblique muscle.
The shape, size, and orientation of the EOM from origin to insertion form the basis for the eye movements that result from their contraction ( Table 7.1 ). Although the effect of contraction of each EOM will be described separately, it is important to remember that they work in a coordinated fashion, maintaining significant tension or “tonus” even when the eye is in primary position and thus presumably “at rest.” ,
| Muscle | Primary Action | Secondary Action | Motor Innervation | Antagonists | Synergists |
|---|---|---|---|---|---|
| Lateral rectus | Abduction | None | Abducens nerve (CN VI) | Medial rectus | Superior and inferior oblique muscle |
| Medial rectus | Adduction | None | Oculomotor nerve (CN III, inferior division) | Lateral rectus | Superior and inferior rectus muscle |
| Superior rectus | Elevation | Adduction Intorsion | Oculomotor nerve (CN III, superior division) | Inferior rectus | Medial and inferior rectus muscle Superior oblique muscle |
| Inferior rectus | Depression | Adduction Extorsion | Oculomotor nerve (CN III, inferior division) | Superior rectus |
|
| Superior oblique | Intorsion | Depression Abduction | Trochlear nerve (CN IV) | Inferior oblique |
|
| Inferior oblique | Extorsion | Elevation Abduction | Oculomotor nerve (CN III, inferior division) | Superior oblique |
|
Eye movements in the horizontal plane are controlled by the medial and lateral rectus muscles, agonist-antagonist pairs with opposing primary functions; the medial rectus adducts the eye, and the lateral rectus abducts the eye. Vertical movements are more complex. The superior and inferior rectus muscles have a more complex action on the direction of eye movements because the bony orbits are not parallel to each other ( Fig. 7.2 ). In primary gaze, both the superior and inferior recti are angled laterally at approximately 22.5 degrees from the sagittal plane. The primary action of the superior rectus muscle is elevation, but it also adducts and intorts the eye ( Table 7.1 ; Fig. 7.4 ). Intorsion is where the superior pole of the eye rotates medially. Thus, if the superior rectus muscle was acting alone, the direction of gaze would be superior and medial, that is, up and in toward the nose. The inferior rectus is parallel to the superior rectus but inserts on the inferior surface of the globe. It primarily depresses the eye, but also adducts and extorts ( Fig. 7.4 ); extorsion is rotation of the superior pole of the eye laterally.
Owing to its insertion posterior to the equator of the globe, as well as the vector of force directed by the position of the trochlea in the superior and medial orbit, the superior oblique mainly intorts the eye ( Table 7.1 ; Fig. 7.4 ). It also depresses and abducts. Thus, working unilaterally, gaze would be directed down and out. As the inferior oblique muscle parallels the superior oblique, but inserts on the inferior surface of the globe, its primary function is extorsion of the eye ( Table 7.1 ; Fig. 7.4 ); it also elevates and abducts. For accurate positioning of the visual world on the fovea, activity of all the EOM must be highly coordinated by the ocular motor control systems in the brain.
Cranial nerve innervation
The optic foramen is located within the lesser wing of the sphenoid bone at the orbital apex, through which runs the optic nerve (cranial nerve II, CN II) and the ophthalmic artery. Between the greater and lesser wings of the sphenoid bone is the superior orbital fissure. The structures entering the orbit through this fissure are divided by the tendinous annulus (formerly the annulus of Zinn). Structures that enter the orbit superior to the annulus are the lacrimal and frontal nerves, both sensory branches of the ophthalmic division of the trigeminal nerve (CN V); the trochlear nerve (CN IV), motor nerve to the superior oblique muscle; and the superior ophthalmic veins ( Fig. 7.5 ). A large number of structures course through the annulus, entering into an area within what is referred to as the muscle cone. These vessels and nerves are surrounded by the EOM and their connective tissue ensheathments. Within the annulus, the superior orbital fissure admits the superior and inferior divisions of the oculomotor nerve (CN III), which is the motor nerve to the inferior rectus, inferior oblique, medial rectus, superior rectus and levator palpebrae superioris muscles, and the abducens nerve (CN VI), the motor nerve to the lateral rectus muscle. The nasociliary nerve is also located in this region, and it is a sensory branch of the ophthalmic division of the trigeminal nerve (CN V). Entering the orbit through the superior orbital fissure inferior to the annulus is the inferior ophthalmic vein that communicates with the pterygoid plexus of veins inferiorly. On the floor of the orbit is the inferior orbital fissure, which admits small branches of the zygomatic nerve, a sensory nerve innervating the lateral midface as well as lacrimal rami, carrying parasympathetic innervation from the facial nerve (CN VII) to the lacrimal gland.
Once inside the bony orbit, the motor nerve branches of CN III, CN IV, and CN VI course anteriorly toward the muscles they innervate. The superior division of CN III innervates the superior rectus muscle and continues superiorly to innervate the levator palpebrae superioris. The inferior division of CN III innervates the medial and inferior rectus muscles, and the latter branch continues inferiorly to innervate the inferior oblique. All nerve branches of CN III enter the muscles on their deep surfaces within the muscle cone. CN VI also enters the lateral rectus muscle on its deep surface. Of the motor nerves, only the trochlear nerve, CN IV, enters the orbit outside the tendinous annulus innervating the superior oblique muscle on its superior or lateral surface ( Fig. 7.5 ). All motor nerves that innervate the EOM enter the body of the muscles at their posterior third ( Fig. 7.5 ).
Neuromuscular junctions (NMJs) are the specialized sites of communication between a nerve and the myofibers it innervates. In noncranial skeletal muscle, NMJs usually form in the middle one-third of each myofiber. The NMJs formed by the cranial motor nerves with individual EOM myofibers display some distinct differences compared with those in noncranial skeletal muscle. Similar to body muscles, the EOM have singly innervated myofibers with NMJs referred to as “ en plaque ” endings ( Fig. 7.6 ). However, the en plaque NMJs in EOM are smaller and less complicated structurally than those in noncranial skeletal muscles. In addition, the EOM have multiply innervated myofibers with neuromuscular junctions referred to as “ en grappe ” endings ( Fig. 7.6 ). These are a linear array of small synaptic contacts often found toward the ends of individual myofibers, but can be continuous along the length of individual myofibers. The en grappe NMJ contacts are structurally simple. Thus, in EOM a single myofiber can have an en plaque NMJ somewhere along the middle one-third and also have multiple en grappe endings along the tapered ends ( Fig. 7.6 ). Some myofibers in EOM that express the slow tonic myosin heavy chain isoform (MYH14) have en grappe endings along their entire myofiber length and do not have an en plaque ending.
Acetylcholine receptors found within NMJs in skeletal muscle are composed of five subunits. In developing noncranial muscle there are two alpha, one beta, one gamma, and one delta subunits (α2βγδ), and in the adult the gamma subunit is replaced with the epsilon subunit. This subunit pattern is found in most en plaque endings within the extraocular muscles. In contrast, in adult EOM the majority of the en grappe endings express the “immature” gamma subunit, rather than the epsilon subunit of mature endings. , Both the en plaque and en grappe endings in the EOM can coexpress both the epsilon and gamma subunits ; this appears to be unique to EOM based on studies performed thus far. Owing to the nature of EOM myofiber length, as discussed in a following section, NMJs can be seen throughout the origin-to-insertional length of EOM in most species where this has been examined. , This is in contrast to most limb skeletal muscles, which have a motor endplate zone, an NMJ band that is fairly contained within a defined area in the midbelly region of the muscle.
It has generally been assumed that the multiply innervated myofibers are innervated by a single motor neuron, but polyneuronally innervated myofibers are also present. , This means that more than one motor neuron can innervate a single myofiber. This has important implications for EOM physiology and will be discussed in that section.
Orbital connective tissue
A complex framework of connective tissue exists throughout the orbit, and this network has a clear structural organization and consistent pattern ( Fig. 7.7 ). These connective tissue septa contain nerves, vessels, and smooth muscle, and are postulated to play a role in supporting eye movements. Recent studies have confirmed and extended these initial detailed analyses of orbital connective tissue septa to include thickenings around individual EOM called orbital pulleys ( Fig. 7.7 ). These connective and smooth muscle septa and bands constrain the paths of the EOM, changing the vector of force as the EOM contract and stabilize muscle position during movement.
Recent studies demonstrated extensive interconnections between muscle fibers, muscle fascicles, and the muscle epimysium ( Fig. 7.8 ). This meshwork of interconnected peri- and epimysial elements results in demonstrable lateral force transmission during muscle fiber contraction, as evidenced by direct in vitro measurements ( Fig. 7.8 ). These are likely involved in the nonadditive properties of force development, described in more detail in the following section.
Histologic anatomy and physiologic implications
The EOM have a complex anatomy at the microscopic level. The overall cross-sectional areas of their myofibers are extremely small compared to noncranial skeletal muscle. Each EOM is composed of two layers: an outer orbital layer composed of myofibers of extremely small cross-sectional area and an inner global layer with myofibers larger than in the orbital layer but still extremely small compared to noncranial skeletal muscle ( Fig. 7.9 ). Further descriptions will concentrate on human muscle, but the EOM of other mammals have the same general features despite some variations in detail.
In noncranial skeletal muscles, two general fiber types are described, fast and slow, referring mainly to the myosin heavy chain isoforms (MyHC) they express, which in turn determines their shortening velocity. Whether a fiber is “fast” or “slow” is due, in part, to their complement of contractile proteins. Noncranial skeletal muscles that are largely fast MyHC-positive, such as the extensor digitorum longus, have an oxidative metabolism, rapid shortening velocities, and rapid fatigue with activation. Slow MyHC-positive myofibers in noncranial skeletal muscle have a glycolytic metabolism, slower shortening velocities, larger force generation, and are fatigue resistant. The EOM also have these two basic myofiber types. About 85% of the myofibers in both layers in adult EOM are fast MyHC-positive ( Fig. 7.9 ). , The other 15% of the EOM myofibers are positive for the slow MyHC. In contrast to noncranial skeletal muscle, however, the EOM have extremely fast contractile characteristics, yet are also extremely fatigue resistant. Several factors support these apparently contradictory characteristics. Although the vast majority of noncranial skeletal muscles express one of four MyHCs, fast fiber types IIa ( myh2 ), IIx ( myh1 ) and IIb ( myh4 ), and slow type I ( myh7 ) EOM myofibers can contain up to eleven MyHCs with multiple myosins, even within single fibers.
The MyHC expressed in EOM include fast types IIa ( myh2 ), IIx ( myh1 ), and IIb ( myh4 ); MyHCs associated with immaturity in limb and body skeletal muscles—embryonic (developmental) ( myh3 ) and neonatal (fetal) ( myh8 ); slow or type I (which is the same as beta-cardiac myosin in the heart) ( myh7 ); alpha-cardiac ( myh6 ); EOM-specific ( myh13 ); and the slow tonic myosin ( myh7b or myh14 ). Two additional novel myosins also are found in EOM. The first MyHC isoform was found to be expressed in extraocular muscles MYH15 ( myh15 ), but only in orbital layer fibers and muscle spindles. In addition, approximately 20% of the global layer slow MyHC-positive fibers were shown to express the nonmuscle myosin IIB ( myh10 ). This large array of expressed MyHC within the EOM helps explain why its dynamic physiologic properties are significantly different than those in limb muscles. It should be noted that patterns of MyHC composition vary between each EOM, with lateral rectus being the most different. Support for the idea that the MyHC composition may be critical for understanding control of force generation is the physiologic demonstration that there are significant contractile differences between individual muscles. For example, when comparing the medial and lateral rectus muscles, motor units in the medial rectus generate faster twitch contractions and those in lateral rectus generate greater tonic tensions. This concept is critical in understanding the central nervous system (CNS) control of eye movements, as well as eye movement disorders like strabismus.
The expression patterns of EOM myofibers for these MyHC differ significantly between the global and orbital layers ( Fig. 7.9 ). For example, the vast majority of the orbital layer myofibers are positive for developmental myosin (MYH3), yet the global layer only has scattered fibers that immunostain for this isoform ( Fig. 7.9 ). Distinct patterns of differential staining are seen for all other MyHC present in EOM. From a physiologic perspective, this issue becomes even more complex. Approximately 25% of the analyzed cat single lateral rectus motor units, defined as all the fibers innervated by a single motor neuron, had myofibers in both the orbital and global layers. , These bilayer motor units were stronger and faster than motor units contained within single EOM layers, and they tended to be fatigable. Approximately 54% of the global motor units examined were stronger and faster than orbital layer units, in part a reflection of the properties imbued upon the individual myofibers by their contractile proteins.
The expression of individual MyHC also varies along the origin-to-insertional length of each muscle. , , In part this is because many of the EOM myofibers do not run from origin to insertion in both the orbital and global layers , , , ; they can be arranged in parallel or in series, and many branched and/or split myofibers exist ( Fig. 7.10 ). These short myofiber lengths have functional consequences. For example, in a series of studies examining summation of motor forces, individual cat and monkey motor units were stimulated, and the forces each unit produced in the lateral rectus muscle were determined. Then, using simultaneous stimulation, the evoked unit force of other motor units was added to the single motor unit force. In about 25% of the cases in cat and about 85% of the cases in monkey, the measured forces did not add linearly. , Thus, force is “lost” as multiple myofibers are activated, partly due to force dissipation laterally through myomyous junctions and myoconnective tissue connections formed by short myofibers ( Fig. 7.8 ).
In addition, the serial or parallel arrangement of myofibers with different myofibrillar isoforms would significantly affect contractile behavior. This was elegantly demonstrated using sets of single myofibers in vitro, one fast and one slow, that were tied together in series or in parallel. In any given combination of one fast and one slow myofiber, the paired fibers showed a range of forces with greater or lesser fast or slow characteristics. In a fast/slow combination, the fast fiber began to contract prior to the slow fiber, which was then slack and therefore not at its optimal length to generate its full force. Based on these studies, serial or parallel arrangements of myofibers with disparate MyHC isoform composition would result in a range, or continuum, of forces produced by their coactivation. These data suggest that a distributed model of motor recruitment at the CNS level is needed to address the nonlinearity of the effector arm of the system, the EOM themselves.
Individual EOM myofibers are polymorphic and can express more than one MyHC in different regions of each fiber. , , , This is true for a wide variety of species, including human EOM. For example, in both singly and multiply innervated myofibers in the orbital layer in rats, the fiber ends expressed the neonatal MyHC ( myh8 ), but this isoform was completely eliminated at the position of the NMJ, where the fibers immunostained for fast MyHC. In the orbital layer, individual myofibers expressed the embryonic MyHC ( myh3 ) at their fiber ends and the EOM-specific MyHC ( myh13 ) in the NMJ region. Orbital multiply innervated myofibers were found that expressed slow MyHC ( myh7 ) along their entire length, but also expressed embryonic MyHC (myh3) at the fiber ends. Single myofibers in the global layer were found that expressed EOM-specific MyHC ( myh13 ) at the NMJ region, as well as fast MyHC IIb and/or IIx ( myh1 and myh4) . In human EOM, orbital layer myofibers were found that expressed type I MyHC ( myh7 ), and of these ( Fig. 7.11 ), some also expressed slow tonic MyHC ( myh14 ), alpha-cardiac ( myh6 ), and/or embryonic ( myh3 ) or EOM-specific ( myh13 ). , , Physiologic examination of individual multiply innervated myofibers from the orbital layer of rats showed that contractile velocity varied along the length of the fiber, with tonic characteristics at the fiber end and twitch characteristics in the central region near the endplate, the only location where fast MyHC was expressed.
Thus, physiologic properties of the EOM motor units, when activated singly or collectively, reflect these MyHC isoform complexities, as well as differences in individual myofiber length and branching patterns. It should be noted that the EOM show significant activity at all times, even when the eye is directed in what would be considered the off-direction for muscle action. In addition, all motor units participate in all types of eye movements, and there appear to be no motor units that specialize in rapid saccades or slow vergence movements, for example. Presumably, the MyHC composition is a reflection of demands placed on the EOM by the oculomotor control system, and this view is supported by the observation that altering the stimulation frequency to a muscle causes significant changes in MyHC expression. Functional denervation also affects MyHC composition. It is reasonable to suggest that a complex “conversation” is constantly occurring between EOM myofibers and the neurons innervating them, helping them to adapt to ever-changing physiologic demands. Because of these complex MyHC expression patterns and physiologic characteristics, past attempts to classify EOM myofibers into simple groups ultimately fail. Classically, myofibers in noncranial skeletal muscles have been described by their MyHC expression profile (e.g., type IIa or type I). Even in noncranial skeletal muscles, it is becoming increasingly clear that single myofiber MyHC polymorphism is more common than was previously believed. , Another fiber type, called “mismatched,” has been described in both noncranial and cranial skeletal muscle. , Mismatched myofibers include those with “mixed” fast and slow characteristics, and can include fibers with mixtures of fast and slow MyHC or fast or slow MyHC with various regulatory protein such as troponin or myosin-binding protein C that are not of the same “type.” This complexity of protein expression and the heterogeneity of individual myofibers in EOM cannot be overstated. What these studies suggest is that rather than specific “types” of myofibers ( Fig. 7.12 ) in EOM, there is, in fact, a continuum of myofiber types. Each myosin heavy and light chain isoform results in a distinct shortening velocity, which allows for an incredible plasticity in the control of muscle force generation. The modulation of the MyHC patterns with alterations in hormones or innervational changes also compounds the heterogeneity of the EOM myofibers. These adaptive protein changes are extremely rapid, and the control may be at the level of histone modifications or at the translational level controlled by microRNA—known to be upregulated in the EOM. The EOM myofiber continuum hypothesis was suggested previously for other skeletal muscles, including plantaris and masseter. This continuum of myofiber types in EOM combined with the nonlinearity of eye muscle contractile properties would allow CNS control of eye movement position and velocity to be finely tuned as the eyes are moved into an infinite number of positions.
Metabolism
The physiologic properties of the EOM derive their dynamic and unusual characteristics from (1) their expression of specific contractile proteins including, but not limited to, isoforms of MyHC, myosin light chains, tropomyosin, and troponin; (2) the presence of myofibers shorter than the total origin-to-insertional length of each EOM, resulting in fibers connected in parallel or in series; (3) the presence of singly, multiply, and polyneuronally innervated individual myofibers; and (4) adaptations of their metabolic pathways.
The most studied metabolic property in EOM is their calcium handling. Calcium plays a critical role in controlling the duration of muscle contractions. In part, this is controlled by the sarcoplasmic reticulum Ca 2+ -ATPases (SERCA1 and SERCA2) in fast and slow myofibers, respectively, in noncranial skeletal muscle. In contrast to limb skeletal muscle, in the EOM SERCA1 and SERCA2 are coexpressed in the majority of individual myofibers. The EOM contain an abundance of mitochondria, and EOM myofibers appear to use their mitochondria as fast calcium sinks to aid in regulation of calcium. This effectively widens the dynamic range of EOM force production. Owing to their efficient calcium handling, EOM myofibers are resistant to pathologic elevations of intracellular calcium levels.
EOM are resistant to injury and oxidative stress and contain higher levels of superoxide dismutases and glutathione peroxidase activity than limb skeletal muscle. These properties are concordant with the highly aerobic nature of the EOM. Only cardiac muscle has a higher blood flow rate. Despite their highly oxidative metabolism, the EOM are also extremely fatigue-resistant. Unlike noncranial muscles, EOM do not depend on creatine kinase activity for their fatigue resistance ; instead, EOM can utilize lactate as a metabolic substrate during times of increased contractile activity. This further illustrates how the EOM can maintain a highly oxidative metabolism and fatigue resistance simultaneously. Additionally, these two opposite metabolic demands are met by the expression in individual EOM myofibers of both succinate dehydrogenase and alpha-glycerophosphate dehydrogenase, enzymes in the oxidative and glycolytic pathways, respectively. In contrast, these two enzymes are fiber-type specific in limb skeletal muscle. This supports the view that skeletal muscles consist of distinct allotypes relative to body and limb skeletal muscles, and the EOM represent the extreme end relative to its anatomy, innervation, metabolism, and physiologic function.
Another distinctive aspect of EOM function is their ability to undergo a significant level of myonuclear addition and subtraction throughout life, , while simultaneously maintaining their overall size, morphology, and function. Using labeling with the thymidine analog bromodeoxyuridine, activated satellite cells, the myogenic precursor cells of adult muscle, are seen; with sufficient postlabeling intervals, labeled myonuclei are present within existing myofibers in normal adult EOM of rabbits and mice ( Fig. 7.13 ). These new myonuclei are located peripherally, not centrally, indicating that this process of myonuclear addition is different from what occurs during muscle regeneration. This was validated using a PAX7 reporter mouse line, where tdTomato was expressed in PAX7 cells. Myonuclear addition is seen by red fluorescence in fibers where this process has occurred ( Fig. 7.13B ). Although a low level of myonuclear addition occurs in the noncranial muscles examined thus far, it is not at the level of the EOM ( Fig. 7.13B ). The process of myofiber remodeling continues throughout life even in human EOM, as the presence of activated satellite cells, identified by the myogenic lineage marker MYOD, is seen in the EOM specimens from elderly humans. Ongoing and significant levels of myofiber remodeling occurs in other craniofacial muscles as well, suggesting that the differences in genes involved in the development of cranial muscles may play a role in retention of this dynamic process in adult EOM. The control of this process in the adult EOM is unknown.
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