Extraocular muscles have fundamentally distinct properties that make them selectively vulnerable to certain disorders

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DOI: 10.1016/j.nmd.2004.10.002 · Source: PubMed
While skeletal muscles generally perform specific limited roles, extraocular muscles (EOMs) have to be responsive over a wider dynamic range. As a result, EOMs have fundamentally distinct structural, functional, biochemical and immunological properties compared to other skeletal muscles. While these properties enable high fatigue resistance and the rapid and precise control of extraocular motility, they might also explain why EOMs are selectively involved in certain disorders, such as chronic progressive external ophthalmoplegia (CPEO), myasthenia gravis and Graves' ophthalmopathy. This review first gives an overview of the novel myofibre classification in EOMs and then focuses on those properties that might explain why ophthalmoplegia should be so prominent in these disorders.
Extraocular muscles have fundamentally distinct properties
that make them selectively vulnerable to certain disorders
C.Y. Yu Wai Man
, P.F. Chinnery
, P.G. Griffiths
Department of Neurology, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK
Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Received 14 July 2004; received in revised form 22 September 2004; accepted 1 October 2004
While skeletal muscles generally perform specific limited roles, extraocular muscles (EOMs) have to be responsive over a wider
dynamic range. As a result, EOMs have fundamentally distinct structural, functional, biochemical and immunological properties
compared to other skeletal muscles. While these properties enable high fatigue resistance and the rapid and precise control of
extraocular motility, they might also explain why EOMs are selectively involved in certain disorders, such as chronic progressive
external ophthalmoplegia (CPEO), myasthenia gravis and Graves’ ophthalmopathy. This review first gives an overview of the novel
myofibre classification in EOMs and then focuses on those properties that might explain why ophthalmoplegia should be so prominent
in these disorders.
q 2004 Elsevier B.V. All rights reserved.
Keywords: Extraocular muscles; CPEO; myasthenia gravis; Graves’ ophthalmopathy
1. Introduction
There are numerous differences between extraocular
muscles (EOMs) and other skeletal muscles; so much so,
that they can be classified into a distinct allotype separate
from the limb/diaphragm and masticatory muscles [1].
EOMs also have disease susceptibilities that differ from
other skeletal muscles. They are selectively spared in
Duchenne muscular dystrophy and motor neuron disease but
selectively targeted in chronic progressive external ophthal-
moplegia (CPEO), myasthenia gravis and Graves’ ophthal-
mopathy. In this review, we focus on distinctions that exist
between the extraocular muscle and limb muscle allotypes
and speculate as to how these differences might account for
the selective vulnerability of the extraocular muscle allotype
in these disorders Table 1.
2. Types of muscle fibres
There are four types of skeletal muscle fibres: Type I
(slow-twitch, fatigue resistant), Type IIA (fast twitch,
fatigue resistant), Type IIB (fast twitch, fatigable) and
Type IIX (fast twitch, fatigable). Some skeletal muscles
contain predominantly one fibre type that determines their
contractile properties and fatigue resistance (Type I in red
muscles, Type IIA in intermediate muscles and Types IIB
and IIX in white muscles) while others contain a mixture of
different fibre types [2].
On the other hand, EOMs fibres have a novel
classification scheme that is based on their color, location
and innervation. Each EOM is divided into at least two main
layers: a thin orbital layer adjacent to the bony walls of the
orbit and an inner global layer immediately adjacent to the
globe and optic nerve. Moreover, each of these two layers
also consists of both singly and multiply innervated fibres
(Section 3). To deal with terminology, EOMs fibres have
thus been divided into six types: orbital singly innervated,
orbital multiply innervated, global red singly innervated,
0960-8966/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
Neuromuscular Disorders 15 (2005) 17–23
* Corresponding author. Tel.: C44 191 222 8334; fax: C44 191 222
E-mail address: p.f.chinnery@ncl.ac.uk (P.F. Chinnery).
global intermediate singly innervated, global pale singly
innervated and global multiply innervated fibres [3,4].
3. Innervation patterns
Skeletal muscles fibres have a single nerve axon connected
to an en-plaque endplate at the mid-belly of each fibre.
In contrast, only four of the six types of EOM fibres are singly
innervated fibres (SIFs) [2]. The other two types are multiply
innervated fibres (MIFs) with multiple neuromuscular
junctions along the length of each fibre and they possess an
additional type of endplate, the en-grappe endplate, that
arises from one or more nerve fibres [5]. Firing at the synapses
of limb muscle fibres and EOM SIFs leads to an action
potential that creates an all-or-none twitch mode of contrac-
tion. On the other hand, EOM MIFs have a tonic mode of
contraction that is activated focally at each synapse without
generation or propagation of action potentials [6]. These tonic
contractions are slow and graded and only slightly and slowly
increase muscle tension. While global MIFs only have a tonic
mode of contraction, orbital MIFs have a twitch mode of
contraction at mid-belly and a tonic mode of contraction at
their proximal and distal ends [7] (Fig. 1).
In limb muscles, the endplate potential amplitude is
larger than the minimum depolarisation needed to trigger
a propagated action potential. This difference is called the
safety factor. EOM twitch fibres have a lower safety factor
as they have less prominent synaptic folds and therefore one
would predict, fewer acetylcholine receptors on the post-
synaptic membrane [8–11]. The lower safety factor might
thus make EOM twitch fibres more vulnerable to the
reduction in synaptic depolarisation that occurs in myasthe-
nia. On the other hand, EOM tonic fibres have no safety
factor and the force generation is directly proportional to the
membrane depolarisation [10]. Any reduction in synaptic
depolarisation would thus lead to symptomatic muscle
weakness in EOM tonic fibres. Moreover, destruction of the
neuromuscular junction by myasthenia is complement
mediated. Porter et al. found that EOMs express low levels
of decay accelerating factor (Daf) [12] (Section 8.3). As Daf
is an inhibitor of complement deposition at the neuromus-
cular junction, this might allow the complement mediated
response to affect EOMs more severely in myasthenia [11].
4. Motor units and contractile properties
Ocular motor units are an order of magnitude smaller
than limb muscles motor units which is consistent with the
capacity of EOMs to vary their contractile forces by small
increments [2,10]. Moreover, the maximum firing frequen-
cies of ocular motor units in the phasic and sustained phases
are about four times greater than those of limb muscles
motor units [13]. The higher firing frequencies might make
EOMs more prone to the neuromuscular transmission
failure in myasthenia [10]. To allow them to operate at the
higher firing frequencies, EOMs also have faster contractile
properties with their time to peak tension and their one-half
relaxation time being at least half those in limb muscles [2].
Limb movements are executed by the differential
recruitment of motor units for specific subsets of fast and
slow movements [14], and by the frequency modulation of
already active motor units [2]. In contrast, almost every
Table 1
Differences in characteristics between the extraocular muscle and limb muscle allotypes
Limb muscles EOMs
Fibre classification [2] Based on color (red, intermediate, white) Novel classification into 6 fibre types based on color,
location and innervation
Innervation patterns [2,5] Single Single and multiple
Mode of contraction [6,7] Twitch Twitch and tonic
Motor unit size (fibres/motor neuron) [50] 100–2000 13–20
Contractile properties [15,50–55]
Time to peak tension/ms 12.6 (extensor digitorum) 4.4
37.8 (soleus)
One-half relaxation time/ms 8.7 (extensor digitorum) 4.8
54.8 (soleus)
Twitch:tetanic tension ratio 0.2 0.13
Maximum firing frequencies/Hz [13,50] 125 phasic O600 phasic
50 sustained O200 sustained
Recruitment of motor units [2,14,15] Differentially recruited for specific subsets
of fast and slow movements
Wide functional repertoire: almost every motor unit can
participate in saccades, tracking and vergeance movements
Fig. 1. Schematic representation of the modes of contraction in the different
types of EOMs fibres (SIF, singly innervated fibre; MIF, multiply
innervated fibre) [2,6,7].
C.Y. Yu Wai Man et al. / Neuromuscular Disorders 15 (2005) 17–2318
ocular motor unit is able to participate in saccades, tracking
and vergeance movements [2]. At the primary position of
gaze, 70% of ocular motor units are already active and
frequency modulation is the major means of executing eye
movements [15]. EOMs also have a smaller twitch: tetanic
tension ratio than limb muscles which is consistent with
their high capacity to frequency modulate their force output
[15]. The higher firing frequencies, the faster contractile
properties and the higher percentage of recruitment of
ocular motor units in almost every eye movement all
contribute to make the properties of EOMs more energy
demanding than those of limb muscles.
5. Myosin expression
The differences in contractile properties between EOMs
and limb muscles are dictated by their differences in myosin
expression (Table 2). During development, limb muscles
express both of the developmental myosin heavy chain
(MyHC) isoforms, MyHCemb and MyHCneonatal. There-
after, limb muscle fibres express only one of the adult
MyHC isoforms I, IIa, IIb and IIx and it is the type of MyHC
isoform expressed that determines the contractile velocity,
the contractile force and the ATP consumption of the
In contrast, EOMs fibres express almost all known
MyHC isoforms and the expression of more than one MyHC
isoform in single muscle fibres is characteristic of EOMs
[7,16–19]. Firstly, embryonic and neonatal MyHC isoforms
persist in adult EOMs [7,16,18]. Secondly, extraocular
MIFs express the MyHCa-cardiac isoform that is only also
seen in heart and masticatory muscles [20]. Thirdly, EOMs
express the MyHCeom isoform that is otherwise only seen
in laryngeal muscles [21,22]. Briggs et al. also found that
EOMs have longitudinal variation in MyHC expression
along single muscle fibres with the fast MyHC isoforms
being more prominent in the central innervation zone [22].
The high expression of the fast MyHC isoforms in the
central innervation region might thus be the reason why all
EOMs fibres are able to exhibit such fast contractile
properties despite the fact that they have kinetically slower
MyHC isoforms in other fibre sections [22].
6. Structural and metabolic adaptations
EOMs need a higher fatigue resistance to fulfil their more
energy demanding properties [23]. Fuchs et al. demon-
strated that even after continuous strenuous saccadic
movements, the peak saccadic velocities in EOMs only
decreased on average by less than 10% and even then, the
authors argued that this small decrease could largely be
attributed to inattention and lack of motivation of the
subjects [23]. To enjoy such a high fatigue resistance, EOMs
possess a highly developed microvascular bed [4], a higher
blood flow [24], a higher mitochondrial content [25] and a
higher metabolic rate [26].
6.1. Higher mitochondrial content
EOMs have a higher mitochondrial content than skeletal
muscles [25]. Carry et al. also found that the fibres in the
orbital layer have a relatively higher mitochondrial content
than the corresponding fibres in the global layer [25]. Demer
et al. proposed that the differences in mitochondrial content
between the orbital and global layers might be due to their
functional specialisation [27]. In rectus EOMs, the global
layer inserts onto the sclera to mainly rotate the globe while
the orbital layer inserts onto fibrous pulleys in the orbit to
adjust the position of the fibres in the global layer [27].
In order to support the continuous elastic loading of their
fibrous pulley insertions, the orbital layer needs a higher
fatigue resistance and thus has a higher mitochondrial
content. The high dependence of EOMs on oxidative
phosphorylation for their normal functioning is consistent
with their selective vulnerability to the respiratory chain
dysfunction that occurs in mitochondrial disorders such as
CPEO [26].
6.2. Higher metabolic rate
Chang et al. found that mitochondrial DNA (mtDNA)
mutations in mitochondrial disorders seem to be preferen-
tially distributed in tissues with high oxidative metabolisms
such as EOMs [26]. The hypothesis is that the higher
metabolic rate of EOMs, which is needed to fulfil their more
energy demanding properties, might in turn make them
more prone to free radical-mediated enzyme and mtDNA
damage. This theory is consistent with the faster age-related
decline in respiratory chain function that occurs in EOMs
compared to other skeletal muscles [28]. Muller-Hocker
et al. analysed histochemically the age-related increase
in the biochemical defect in cytochrome c oxidase (COX)
in normal EOMs and compared it to those in normal
limb muscles and diaphragms [29,30]. They found that
Table 2
Differences in myosin expression between EOMs and limb muscles [7,16–22]
EOMs Limb
Fast MyHC
MyHCeom O X Laryngeal
Slow MyHC
O X Heart,
MyHCsto O X
MyHC isoforms
MyHCemb O Only
MyHCneonatal O
C.Y. Yu Wai Man et al. / Neuromuscular Disorders 15 (2005) 17–23 19
COX-deficient fibres were already present from the second
decade and that they increased with age in all three types of
muscles. However, the rate of increase was found to be in
overall about six times higher in EOMs compared to the
other muscles [29]. As COX is part of the energy-producing
mechanism that is frequently deficient in mitochondrial
disorders, Muller-Hocker proposed that it might be the
higher age-related progression in COX defect density in
EOMs that selectively predisposes the latter to CPEO
[29,31]. It has been argued that the age-related decline in
respiratory chain function in limb muscles might simply
reflect physical inactivity in older people [32]. However,
this is unlikely to be the case in EOMs as eye movements
continue even in the most sedentary patients.
7. Continuous remodelling
Mature mammalian skeletal myofibres are post-mitotic
in nature but can regenerate in injury by activation of
normally quiescent satellite cells and upregulation of
myogenic regulatory factors such as MyoD. In contrast,
McLoon et al. found that uninjured EOMs contained
satellite cells that are continually dividing [33,34] and
thus proposed that the continuous remodelling in EOMs
might make them selectively vulnerable to certain muscle
disorders such as CPEO [33,35]. The hypothesis is that the
repeated cycling of satellite cells might cause a gradual
accumulation of damaged DNA in the mitochondria and
nuclei of EOMs [35].
However, McLoon’s recent findings have not yet been
confirmed in other studies. Besides, although uninjured
EOMs contained about twice the percentage of MyoD-
positive satellite cells compared to uninjured skeletal
muscles, the frequency of MyoD-positive nuclei found in
uninjured EOMs was rather low with an overall figure of
only about 5 per 100 myofibres [33]. The continuous
remodelling theory of McLoon et al. is also unlikely to be
true unless it can be reconciled with the work of Clark et al.
Using human quadriceps, the latter showed that satellite
cells have low levels of mtDNA mutations and that the
biochemical defect in COX could be reversed by inducing
muscle degeneration with the injection of the local
anaesthetic bupivacaine [36]. According to Clark’s findings,
a higher percentage of activated satellite cells in EOMs
would in fact be a protective mechanism rather than a
predisposing factor in CPEO.
8. Immunological properties
8.1. Orbital components and space
Cell-mediated cytotoxicity against EOMs fibres has been
reported in Graves’ ophthalmopathy [37,38] but the
compelling evidence in the literature points towards orbital
fibroblasts as being the primary targets [39–41].The
proposed pathogenesis is that T-cells recognise the same
antigen on orbital fibroblast as on thyroid follicular cells and
this causes a release of cytokines, e.g. IFN-g and TNF-a.
The latter enhance the expression of immunomodulatory
proteins, e.g. ILA-DR, ICAM-1 and HSP-72, and the end
result is an increased production of glycosaminoglycans by
orbital fibroblasts [39]. As EOMs are located in a restricted
orbital space, the increase in the orbital connective tissue
volume causes compression of EOMs and fibrotic restriction
of their movements and thus leads to the clinical
manifestations of ophthalmopathy [39].
8.2. Acetylcholine receptor (AChR) isoforms
The principal antigenic target in myasthenia gravis is the
nicotinic acetylcholine receptor (AChR) [42]. The latter is a
pentameric protein that exists in two isoforms in mamma-
lian muscles. The structure of the fetal isoform is a
while that of the adult isoform is a
bd3. As adult EOMs co-
express both the fetal and adult AChR isoforms [10,43–45],
this has led to the hypothesis that it might be the g subunit in
the fetal AChR isoform that is selectively targeted in
myasthenia. However, this theory is unlikely to be true
unless it can be reconciled why the levator palpebrae
superioris, which is frequently affected in myasthenia, does
not express the fetal AChR isoform [46].
8.3. Complement-mediated immune response
In the classical pathway, Porter et al. found that the decay
accelerating factor (Daf), which is an inhibitor of the central
C3 amplification convertases, is downregulated in EOMs
compared to other skeletal muscles [12] (Table 3). On the
other hand, Cd59a, which is an inhibitor of complement
deposition on the cell surface, was found to be upregulated
in EOMs. In the alternative pathway, Porter et al. also found
that negative regulators such as complement factor
H-related protein and complement component factor h
(Cfh), were upregulated in EOMs compared to other
Table 3
Differences in complement mediated immune response in EOMs v/s leg
and jaw muscles [12]
Genetic expression
in EOMs v/s leg
and jaw muscles
Decay accelerating factor 1 (Daf1) Downregulated
Decay accelerating factor 2 (Daf2) Downregulated
CD59 antigen (Cd59a) Upregulated
Complement factor H-related
Complement component factor
h (Cfh)
Indicates comparison did not meet criteria for significance between
EOMs and leg muscles.
C.Y. Yu Wai Man et al. / Neuromuscular Disorders 15 (2005) 17–2320
skeletal muscles [12]. As complement activation by both the
classical and alternative pathways has been implicated in
muscle disorders [47–49], these specific patterns of
complement-mediated immune response might contribute
towards the selective vulnerability of EOMs in autoimmune
disorders such as myasthenia gravis and Graves’
9. Conclusions
The selective vulnerability of EOMs to certain disorders
can, in part, be explained by their fundamentally distinct
structural, functional, biochemical and immunological
properties compared to other skeletal muscles (Fig. 2).
The importance of determining the characteristics of EOMs
and the mechanisms that make them selectively vulnerable
to certain disorders is that it will extend our knowledge of
muscle biology but more importantly, it might lead to new
treatment regimes. Unfortunately, the relative inaccessi-
bility of EOMs compared to skeletal muscles and the
relatively smaller volume of tissue available have hampered
research in this area. Recent genome profiling studies
carried out on EOMs lend substantial support to the notion
that they have a unique pattern of gene expression so that
advances in the field of molecular genetics hold the potential
to reveal yet more differences between EOMs and other
skeletal muscles.
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C.Y. Yu Wai Man et al. / Neuromuscular Disorders 15 (2005) 17–23 23
    • "Furthermore, the unique properties of EOMs make them particularly susceptible to certain diseases. For example, EOMs are specifically disordered in chronic progressive external ophthalmoplegia, myasthenia gravis and thyroid-associated orbitopathy (Yu Wai Man et al., 2005). EOM function is also affected by congenital strabismus, peripheral neuronal disorders and central nervous system diseases, for which monitoring EOM dynamics is an important diagnostic indicator. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Members of the Junctional Adhesion Molecule (JAM) family function as cell adhesion molecules and cell surface receptors. The zebrafish genome contains six different jam genes, and jam-b and jam-c were shown to be essential for myoblast fusion during skeletal muscle development. However little is known about jam-b2 expression and function. Results: We isolated the cDNA of zebrafish jam-b2. jam-b2 is expressed specifically in EOMs, jaw muscles and pectoral fins in zebrafish larvae, but not in trunk muscles. The identified jam-b2 expression pattern is supported by the analysis of a zebrafish Gal4-enhancer trap line, in which the coding sequence of the transcriptional activator KalTA4 together with a Gal4-dependent UAS-mCherry expression cassette was inserted into the jam-b2 locus. Intercrosses with an UAS:EGFP strain proves the possibility for targeting transgene expression to EOMs, jaw muscles and fins. Finally, we characterized the concerted contraction pattern of EOMs in larvae performing an optokinetic response. Conclusions: The expression pattern of jam-b2 suggests that it may contribute different properties to EOMs, jaw muscles and pectoral fins. The jam-b2:KalTA4-UAS-mCherry transgenic strain serves a dual role as both a reporter for these muscles and as a valuable genetic tool for targeting transgene expression to EOMs. This article is protected by copyright. All rights reserved.
    Article · Sep 2015
    • "Acquired cases are either due to trauma or surgery, which causes scarring/avulsion of trochlea. When congenital, the superior oblique muscle belly is also atrophic as may be demonstrated by high resolution MRI [44] (Figures 17 and 18). Isolated myositis of EOM: Isolated myositis of extraocular muscle is usually a subgroup of idiopathic orbital inflammatory syndrome. "
    [Show abstract] [Hide abstract] ABSTRACT: Neuro-ophthalmological pathologies require dedicated imaging studies for proper localisation and appropriate diagnosis. Technical advancements in MRI and CT have facilitated early diagnosis and treatment of various neuro-ophthalmological disorders. This review article has tried to focus on specific imaging techniques and imaging features of these neuro-ophthalmological disorders.
    Article · Jan 2015 · Developmental Dynamics
    • "EOMs have a unique myofibrillar protein isoform composition reflecting their structural and functional properties [8]. Compared with skeletal muscle, EOMs have smaller motor unit sizes, higher motor neuron discharge rates, higher blood flow with higher mitochondrial volume fractions which can suggest that the energy requests and susceptibility to mitochondrial dysfunction are higher as compared with skeletal muscle [2,9]. Due to the high blood flow and vascularisation, inflammatory blood cells can access more easily this specialized body compartment [2, 10]. "
    [Show abstract] [Hide abstract] ABSTRACT: We report the case of a 43 year old man who presented recurrent left abducens palsy. His medical history included arterial hypertension, ischemic cardiomiopathy, dyslipidemia, rhinitis, maxillary sinusitis. Physical examination revealed a overweight patient, horizontal gaze diplopia, left nerve VI paresis, mild left retro-orbital pain. The orbital MRI also didn't offer new information: mild external edema on the left eye, with normal tendon aspect, no thickening or enhancement of the muscle belly and also normal aspect of the bony orbit. Recurrent palsy of EOMs can be caused in rare cases by ocular myositis.
    Full-text · Article · May 2014
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