John D. Porter

Biological organization of the extraocular muscles

Extraocular muscle is fundamentally distinct from other skeletal muscles. Here, we review the biological organization of the extraocular muscles with the intent of understanding this novel muscle group in the context of oculomotor system function. The specific objectives of this review are threefold. The first objective is to understand the anatomic arrangement of the extraocular muscles and their compartmental or layered organization in the context of a new concept of orbital mechanics, the active pulley hypothesis. The second objective is to present an integrated view of the morphologic, cellular, and molecular differences between extraocular and the more traditional skeletal muscles. The third objective is to relate recent data from functional and molecular biology studies to the established extraocular muscle fiber types. Developmental mechanisms that may be responsible for the divergence of the eye muscles from a skeletal muscle prototype also are considered. Taken together, a multidisciplinary understanding of extraocular muscle biology in health and disease provides insights into oculomotor system function and malfunction. Moreover, because the eye muscles are selectively involved or spared in a variety of neuromuscular diseases, knowledge of their biology may improve current pathogenic models of and treatments for devastating systemic diseases.

Eye muscle sparing by the muscular dystrophies: Lessons to be learned?

The devastating consequences of the various muscular dystrophies are even more obvious when a muscle or muscle group is spared. The study of the exceptional cell or tissue responses may prove to be of considerable value in the analysis of disease mechanisms. The small muscles responsible for eye movements, the extraocular muscles, have functional and morphological characteristics that set them aside from other skeletal muscles. Notably, these muscles are clinically unaffected in Duchenne/Becker, limb‐girdle, and congenital muscular dystrophies, pathologies due to a broken mechanical or signaling linkage between the cytoskeleton and the extracellular matrix. Uncovering the strategies used by the extraocular muscles to “naturally” protect themselves in these diseases should contribute to knowledge of both pathogenesis and treatment. We propose that careful investigation of the cellular determinants of extraocular muscle‐specific properties may provide insights into how these muscles avoid or adapt to the cascade of events leading to myofiber degeneration in the muscular dystrophies. Microsc. Res. Tech. 48:192–203, 2000.

Extraocular Muscle: Cellular Adaptations for a Diverse Functional Repertoire

Abstract: Oculomotor control systems are considerably more complex and diverse than are spinal skeletomotor systems. Moreover, individual skeletal muscles are frequently functional role‐specific, while all extraocular muscles operate across a very wide dynamic range. We contend that the novel phenotype of the extraocular muscles is a direct consequence of the functional demands imposed upon this muscle group by the central eye movement controllers. This review highlights five basic themes of extraocular muscle biology that set them apart from more typical skeletal muscles, specifically, the (a) novel innervation pattern, (b) heterogeneity in contractile proteins, (c) structural and functional compartmentalization of the rectus and oblique muscles, (d) diversity of extraocular muscle fiber types, and (e) relationship between the novel muscle phenotype and the differential response of these muscles in neuromuscular and endocrine disease. Finally, new data from broad genome‐wide profiling studies are reviewed, with global gene expression patterns lending substantial support to the notion that the extraocular muscles are fundamentally different from traditional skeletal muscle. This novel eye muscle phenotype represents an adaptation that exploits the full range of variability in skeletal muscle to meet the needs of visuomotor systems.

Vestibulo-ocular pathways modulate extraocular muscle myosin expression patterns

Abstract The genetic and epigenetic influences that establish and maintain the unique phenotype of the extraocular muscles (EOMs) are poorly understood. The vestibulo-ocular reflex (VOR) represents an important input into the EOMs, as it stabilizes eye position relative to the environment and provides a platform for function of all other eye movement systems. A role for vestibular cues in shaping EOM maturation was assessed in these studies using the ototoxic nitrile compound 3’,3’-iminodipropionitrile (IDPN) to eliminate the receptor hair cells that drive the vestibulo-ocular reflex. Intraperitoneal injections of IDPN were followed by a 2-week survival period, after which myosin heavy chain (MyHC) analysis of the EOMs was performed. When IDPN was administered to juvenile rats, the proportion of eye muscle fibers expressing developmental and fast myosins was increased, while EOM-specific MyHC mRNA levels were downregulated. By contrast, IDPN treatment in adult rats affected only the proportion of fibers expressing developmental MyHC isoforms, leaving the EOM-specific MyHC mRNA unaltered. These data provide evidence that the VOR modulates EOM-specific MyHC expression in development. The lack of significant changes in EOM-specific MyHC expression in adult EOM following IDPN administration suggests that there may be a critical period during development when alterations in vestibular activity have significant and permanent consequences for the eye muscles.

Conservation of Synapse-Signaling Pathways at the Extraocular Muscle Neuromuscular Junction

The cell and molecular biology of extraocular muscle (EOM) is distinct from other skeletal muscles.1,2 Novel aspects of the innervation pattern of EOM include: high motoneuron discharge rates, presence of multiply innervated muscle fiber types in the adult, retention of embryonic acetylcholine receptor isoforms at some neuromuscular junctions (NMJs), absence of significant postjunctional membrane foldings at most NMJs, and sensitivity of EOM to neuromuscular transmission disorders (myasthenia gravis) and distinct response to botulinum toxin. The formation and maturation of the NMJ require a series of inductive interactions between axon and muscle fiber. These interactions culminate in the juxtaposition of a highly specialized nerve terminal with an elaborate postsynaptic apparatus.3,4 The sarcolemmal DGC and its associated proteins are central in this process of synapse formation and stabilization.5,6 The central hypothesis of this work was that the unique phenotype, and functional properties, of EOM may require muscle group-specific adaptations to organize and maintain the NMJ. Therefore, the signaling and sarcolemmal organization at the NMJ may differ between EOM singly (SIF) and multiply innervated fiber types (MIF) and between EOM and other skeletal muscles.

The Oculomotor System

The oculomotor system has the dual tasks of maintaining stability of eye position and directing eye movements toward novel features of our environment. This system operates under very fine tolerances. The fovea, the region of highest visual acuity on the retina, “sees” only an area about the size of a quarter held at arm length. Thus, the eyes must be precisely directed toward an object of interest and held in that position for precise and clear vision. Drift of the eyes produces blurred vision, and misalignment of both eyes (strabismus) causes double vision, or diplopia.