Extraocular Muscle Susceptibility in Neuromuscular Disease

Abstract & Commentary

Synopsis: 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.

Source: Yu Wai Man CY, et al. Extraocular Muscles Have Fundamentally Distinct Properties That Make Them Selectively Vulnerable to Certain Disorders. Neuromuscular Disorders 2005;15;17-23.

Extraocular muscles (EOM) are preferentially involved in a number of neuromuscular disorders. Several factors possibly contribute to this phenomenon. Compared to skeletal muscle fibers that are simply classified as either Type I (slow twitch, fatigue resistant) or Type II (A-fast twitch, fatigue resistant, and B and X- fast twitch, fatigable), EOMs are more complex. Classified into 6 types, based on color, location, and innervation, they include 1) orbital singly innervated fibers, 2) orbital multiply innervated fibers, 3) global red singly innervated fibers, 4) global intermediate singly innervated fibers, 5) global pale singly innervated fibers, and 6) global multiply innervated fibers. Whereas skeletal muscle cells invariably have a single axon innervation, 2 types of EOMs (orbital and global, multiply innervated fibers (MIFs)) have en-grappe endplates arising from several nerve fibers, allowing for a tonic, slow, and graded mode of contraction. This slowly increases muscle tension, causing contraction at the 2 ends of the muscle fiber, rather than at the muscle belly. Global MIFs only contract in the tonic mode, but orbital MIFs contract at both ends, as well as at the muscle belly. Unlike skeletal muscle that has a high safety factor built into the end plate potential, EOM twitch fibers have a smaller safety factor, and this may contribute to their vulnerability in myasthenia.

Motor units are smaller in the eye than in limb muscles, comprising 13-20 muscle fibers/motor neuron, compared to 100-2000 in the latter. Firing frequencies are 4-fold higher in the former, perhaps explained by their high expression of fast myosin heavy chain isoforms. Additionally, almost every EOM motor unit can participate in eye movements, compared to the recruitment principles in limb muscles. These factors engender greater energy demands in EOMs that are addressed by their higher mitochondrial content and blood flow, and may explain why EOMs are preferentially affected in neuromuscular disorders.

Commentary

In contrast, EOMs are spared in muscular dystrophy, despite sharing the same molecular deficiency as skeletal muscle. Mechanical stability at the sarcolemma is attributed to the dystrophin-glycoprotein complex, which links intracellular and extracellular matrix proteins to produce scaffolding that maintains cell integrity. Mice with limb girdle muscular dystrophy consequent to deficiency of sarcoglycan maintain intact EOMs, despite involvement of limb and diaphragm muscles (Neuromuscular Disorders. 2000:11:197-207). Accessory ocular muscles including the levator palpebrae superioris and retractor bulbi (responsible for posterior displacement of the eye) were affected to a degree intermediate between the EOMs and limb muscles, demonstrating modestly increased numbers of centrally nucleated muscle fibers without evidence of muscle necrosis, compensatory hypertrophy, or accumulation of adipose or fibrotic tissue in the endomysium. Despite secondary displacement of EOM and sarcoglycan by the sarcoglycan deficit, no functional abnormality was evident. How EOMs remain above the fray, despite sharing the mutational abnormality, remains an enigma. — Michael Rubin

Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.