Publications by authors named "Linda K McLoon"

69 Publications

Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement.

Biomolecules 2021 Jan 29;11(2). Epub 2021 Jan 29.

Immusoft Corp, Minneapolis, MN 55413, USA.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.
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http://dx.doi.org/10.3390/biom11020189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911293PMC
January 2021

Eye alignment changes caused by sustained GDNF treatment of an extraocular muscle in infant non-human primates.

Sci Rep 2020 07 17;10(1):11927. Epub 2020 Jul 17.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA.

The ability of sustained treatment of a single extraocular muscle with glial cell line-derived neurotrophic factor (GDNF) to produce a strabismus in infant non-human primates was tested. Six infant non-human primates received a pellet containing GDNF, releasing 2 µg/day for 90 days, on one medial rectus muscle. Eye alignment was assessed up to 6 months. Five of the six animals showed a slow decrease in eye misalignment from the significant exotropia present at birth, ending with approximately 10° of exotropia. Controls became orthotropic. Misalignment averaged 8° three months after treatment ended. After sustained GDNF treatment, few changes were seen in mean myofiber cross-sectional areas compared to age-matched naïve controls. Neuromuscular junction number was unaltered in the medial rectus muscles, but were significantly reduced in the untreated lateral recti. Neuromuscular junctions on slow fibers became multiply innervated after this sustained GDNF treatment. Pitx2-positive cells significantly decreased in treated and contralateral medial rectus muscles. Our study suggests that balanced GDNF signaling plays a role in normal development and maintenance of orthotropia. Sustained GDNF treatment of one medial rectus muscle resulted in a measurable misalignment largely maintained 3 months after treatment ended. Structural changes suggest mechanisms for producing an imbalance in muscle function.
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http://dx.doi.org/10.1038/s41598-020-68743-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368047PMC
July 2020

Morphological Differences in the Inferior Oblique Muscles from Subjects with Over-elevation in Adduction.

Invest Ophthalmol Vis Sci 2020 06;61(6):33

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Purpose: We examined inferior oblique muscles from subjects with over-elevation in adduction for characteristics that might shed light on the potential mechanisms for their abnormal eye position.

Methods: The inferior oblique muscles were obtained at the time of surgery in subjects diagnosed with either primary inferior oblique overaction or Apert syndrome. The muscles were frozen and processed for morphometric analysis of myofiber size, central nucleation, myosin heavy chain (MyHC) isoform expression, nerve density, and numbers of neuromuscular junctions per muscle section.

Results: The inferior oblique muscles from subjects with Apert Syndrome were smaller, and had a much more heterogeneous profile relative to myofiber cross-sectional area compared to controls. Increased central nucleation in the Apert syndrome muscles suggested on-going myofiber regeneration or reinnervation over time. Complex changes were seen in the MyHC isoform patterns that would predict slower and more sustained contractions than in the control muscles. Nerve fiber densities were significantly increased compared to controls for the muscles with primary inferior oblique overaction and Apert syndrome that had no prior surgery. The muscles from Apert syndrome subjects as well as those with primary inferior oblique overaction with no prior surgery had significantly elevated numbers of neuromuscular junctions relative to the whole muscle area.

Conclusions: The muscles from both sets of subjects were significantly different from control muscles in a number of properties examined. These data support the view that despite similar manifestations of eye misalignment, the potential mechanism behind the strabismus in these subjects is significantly different.
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http://dx.doi.org/10.1167/iovs.61.6.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415317PMC
June 2020

Electroretinographic Abnormalities and Sex Differences Detected with Mesopic Adaptation in a Mouse Model of Schizophrenia: A and B Wave Analysis.

Invest Ophthalmol Vis Sci 2020 02;61(2):16

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Purpose: Mesopic flash electroretinography (fERG) as a tool to identify N-methyl-d-aspartate receptor (NMDAR) hypofunction in subjects with schizophrenia shows great potential. We report the first fERG study in a genetic mouse model of schizophrenia characterized by NMDAR hypofunction from gene silencing of serine racemase (SR) expression (SR-/-), an established risk gene for schizophrenia. We analyzed fERG parameters under various background light adaptations to determine the most significant variables to allow for early identification of people at risk for schizophrenia, prior to onset of psychosis. SR is a risk gene for schizophrenia, and negative and cognitive symptoms antedate the onset of psychosis that is required for diagnosis.

Methods: The scotopic, photopic, and mesopic fERGs were analyzed in male and female mice in both SR-/- and wild-type (WT) mice and also analyzed for sex differences. Amplitude and implicit time of the a- and b-wave components, b-/a-wave ratio, and Fourier transform analysis were analyzed.

Results: Mesopic a- and b-wave implicit times were significantly delayed, and b-wave amplitudes, b/a ratios, and Fourier transform were significantly decreased in the male SR-/- mice compared to WT, but not in female SR-/- mice. No significant differences were observed in photopic or scotopic fERGs between genotype.

Conclusions: The fERG prognostic capability may be improved by examination of background light adaptation, a larger array of light intensities, considering sex as a variable, and performing Fourier transform analyses of all waveforms. This should improve the ability to differentiate between controls and subjects with schizophrenia characterized by NMDAR hypofunction.
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http://dx.doi.org/10.1167/iovs.61.2.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326504PMC
February 2020

Electoretinographic evidence of retinal ganglion cell-dependent function in schizophrenia.

Schizophr Res 2020 05 12;219:34-46. Epub 2019 Oct 12.

Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, United States of America; Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States of America; Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, United States of America.

Schizophrenia is a complex disorder that is diagnosed mainly with clinical observation and evaluation. Recent studies suggest that many people with schizophrenia have abnormalities in the function of the N-methyl-d-aspartate receptor (NMDAR). The retina is part of the central nervous system and expresses the NMDAR, raising the possibility of the early detection of NMDAR-related schizophrenia by detecting differences in retinal function. As a first-step, we used two non-invasive outpatient tests of retinal function, the photopic negative response (PhNR) of the light-adapted flash-electroretinogram (PhNR-fERG) and the pattern ERG (PERG), to test individuals with schizophrenia and controls to determine if there were measurable differences between the two populations. The PhNR-fERG showed that males with schizophrenia had a significant increase in the variability of the overall response, which was not seen in the females with schizophrenia. Additionally at the brightest flash strength, there were significant increases in the PhNR amplitude in people with schizophrenia that were maximal in controls. Our results show measurable dysfunction of retinal ganglion cells (RGCs) in schizophrenia using the PhNR-fERG, with a good deal of variability in the retinal responses of people with schizophrenia. The PhNR-fERG holds promise as a method to identify individuals more at risk for developing schizophrenia, and may help understand heterogeneity in etiology and response to treatment.
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http://dx.doi.org/10.1016/j.schres.2019.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442157PMC
May 2020

Effects of Repeated Eyelid Injections with Botulinum Toxin A on Innervation of Treated Muscles in Patients with Blepharospasm.

Curr Eye Res 2019 03 23;44(3):257-263. Epub 2018 Nov 23.

a Department of Ophthalmology and Visual Neurosciences , University of Minnesota , Minneapolis , Minnesota , USA.

Purpose: To assess changes in innervation and muscle morphology after repeated botulinum toxin A injections in subjects with benign essential blepharospasm.

Methods: Surgical waste specimens were processed for histologic examination of nerve fibers, neuromuscular junctions, fiber size, and central nucleation and compared to age matched controls and to two subjects with blepharospasm that had not received botulinum toxin A injections.

Results: There was a significant increase in amount of nerve fibers and numbers of neuromuscular junctions in the orbicularis oculi muscles from subjects with blepharospasm treated repetitively with botulinum toxin A. In addition there was a significant decrease in mean muscle fiber cross-sectional area and an increase in central nucleation. The specimens from the subjects with only blepharospasm had the same density of nerves but had intermediate levels of neuromuscular junctions.

Conclusions: These data suggest that repeated injections of botulinum toxin A has an effect on nerve and neuromuscular junction numbers, which are partly mirrored in orbicularis oculi muscle from subjects with blepharospasm only. These studies suggest the potential for modulating these changes in order to extend the duration of effectiveness of botulinum toxin.
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http://dx.doi.org/10.1080/02713683.2018.1543707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397080PMC
March 2019

Visualizing Neuronal Adaptation Over Time After Treatment of Strabismus.

Invest Ophthalmol Vis Sci 2018 10;59(12):5022-5024

Department of Ophthalmology and Visual Neurosciences, Minneapolis, Minnesota, United States.

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http://dx.doi.org/10.1167/iovs.18-25651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188464PMC
October 2018

Muscle Satellite Cell Cross-Talk with a Vascular Niche Maintains Quiescence via VEGF and Notch Signaling.

Cell Stem Cell 2018 10;23(4):530-543.e9

Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, USA; Paul & Sheila Wellstone Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, MN, USA; Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA. Electronic address:

Skeletal muscle is a complex tissue containing tissue resident muscle stem cells (satellite cells) (MuSCs) important for postnatal muscle growth and regeneration. Quantitative analysis of the biological function of MuSCs and the molecular pathways responsible for a potential juxtavascular niche for MuSCs is currently lacking. We utilized fluorescent reporter mice and muscle tissue clearing to investigate the proximity of MuSCs to capillaries in 3 dimensions. We show that MuSCs express abundant VEGFA, which recruits endothelial cells (ECs) in vitro, whereas blocking VEGFA using both a vascular endothelial growth factor (VEGF) inhibitor and MuSC-specific VEGFA gene deletion reduces the proximity of MuSCs to capillaries. Importantly, this proximity to the blood vessels was associated with MuSC self-renewal in which the EC-derived Notch ligand Dll4 induces quiescence in MuSCs. We hypothesize that MuSCs recruit capillary ECs via VEGFA, and in return, ECs maintain MuSC quiescence though Dll4.
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http://dx.doi.org/10.1016/j.stem.2018.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178221PMC
October 2018

Demystifying Graduate School: Navigating a PhD in Neuroscience and Beyond.

J Undergrad Neurosci Educ 2018 15;16(3):A203-A209. Epub 2018 Sep 15.

Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455.

The decision to apply to a PhD-granting graduate program is both exciting and daunting. Understanding what graduate programs look for in an applicant will increase the chance of successful admission into a PhD program. It is also helpful for an applicant to understand what graduate training will look like once they matriculate into a PhD program to ensure they select programs that will help them reach their career objectives. This article focuses specifically on PhD programs in neuroscience, and while we use our program, the Graduate Program in Neuroscience at the University of Minnesota, as an example, most of what we describe is applicable to biomedical graduate programs generally. In order to ensure that our description of graduate programs is typical of neuroscience graduate programs generally, we surveyed the online websites of 52 neuroscience graduate programs around the U. S. and include our observations here. We will examine what graduate schools look for in an applicant, what to expect once admitted into a PhD graduate program, and the potential outcomes for those who successfully complete their PhD in neuroscience.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153002PMC
September 2018

Changing muscle function with sustained glial derived neurotrophic factor treatment of rabbit extraocular muscle.

PLoS One 2018 24;13(8):e0202861. Epub 2018 Aug 24.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.

Recent microarray and RNAseq experiments provided evidence that glial derived neurotrophic factor (GDNF) levels were decreased in extraocular muscles from human strabismic subjects compared to age-matched controls. We assessed the effect of sustained GDNF treatment of the superior rectus muscles of rabbits on their physiological and morphological characteristics, and these were compared to naïve control muscles. Superior rectus muscles of rabbits were implanted with a sustained release pellet of GDNF to deliver 2μg/day, with the contralateral side receiving a placebo pellet. After one month, the muscles were assessed using in vitro physiological methods. The muscles were examined histologically for alteration in fiber size, myosin expression patterns, neuromuscular junction size, and stem cell numbers and compared to age-matched naïve control muscles. GDNF resulted in decreased force generation, which was also seen on the untreated contralateral superior rectus muscles. Muscle relaxation times were increased in the GDNF treated muscles. Myofiber mean cross-sectional areas were increased after the GDNF treatment, but there was a compensatory increase in expression of developmental, neonatal, and slow tonic myosin heavy chain isoforms. In addition, in the GDNF treated muscles there was a large increase in Pitx2-positive myogenic precursor cells. One month of GDNF resulted in significant extraocular muscle adaptation. These changes are interesting relative to the decreased levels of GDNF in the muscles from subjects with strabismus and preliminary data in infant non-human primates where sustained GDNF treatment produced a strabismus. These data support the view that GDNF has the potential for improving eye alignment in subjects with strabismus.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202861PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108505PMC
February 2019

Composition, Architecture, and Functional Implications of the Connective Tissue Network of the Extraocular Muscles.

Invest Ophthalmol Vis Sci 2018 01;59(1):322-329

Department of Clinical Science, Ophthalmology, Umeå University, Umeå, Sweden.

Purpose: We examined the pattern and extent of connective tissue distribution in the extraocular muscles (EOMs) and determined the ability of the interconnected connective tissues to disseminate force laterally.

Methods: Human EOMs were examined for collagens I, III, IV, and VI; fibronectin; laminin; and elastin using immunohistochemistry. Connective tissue distribution was examined with scanning electron microscopy. Rabbit EOMs were examined for levels of force transmission longitudinally and transversely using in vitro force assessment.

Results: Collagens I, III, and VI localized to the endomysium, perimysium, and epimysium. Collagen IV, fibronectin, and laminin localized to the basal lamina surrounding all myofibers. All collagens localized similarly in the orbital and global layers throughout the muscle length. Elastin had the most irregular pattern and ran longitudinally and circumferentially throughout the length of all EOMs. Scanning electron microscopy showed these elements to be extensively interconnected, from endomysium through the perimysium to the epimysium surrounding the whole muscle. In vitro physiology demonstrated force generation in the lateral dimension, presumably through myofascial transmission, which was always proportional to the force generated in the longitudinally oriented muscles.

Conclusions: A striking connective tissue matrix interconnects all the myofibers and extends, via perimysial connections, to the epimysium. These interconnections are significant and allow measurable force transmission laterally as well as longitudinally, suggesting that they may contribute to the nonlinear force summation seen in motor unit recording studies. This provides strong evidence that separate compartmental movements are unlikely as no region is independent of the rest of the muscle.
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http://dx.doi.org/10.1167/iovs.17-23003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773232PMC
January 2018

Extraocular Muscle Repair and Regeneration.

Curr Ophthalmol Rep 2017 Sep 16;5(3):207-215. Epub 2017 Jun 16.

Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota.

Purpose Of Review: The goal of this review is to summarize the unique regenerative milieu within mature mammalian extraocular muscles (EOMs). This will aid in understanding disease propensity for and sparing of EOMs in skeletal muscle diseases as well as the recalcitrance of the EOM to injury.

Recent Findings: The EOMs continually remodel throughout life and contain an extremely enriched number of myogenic precursor cells that differ in number and functional characteristics from those in limb skeletal muscle. The EOMs also contain a large population of Pitx2-positive myogenic precursor cells that provide the EOMs with many of their unusual biological characteristics, such as myofiber remodeling and skeletal muscle disease sparing. This environment provides for rapid and efficient remodeling and regeneration after various types of injury. In addition, the EOMs show a remarkable ability to respond to perturbations of single muscles with coordinated changes in the other EOMs that move in the same plane.

Summary: These data will inform Ophthalmologists as they work toward developing new treatments for eye movement disorders, new approaches for repair after nerve or direct EOMs injury, as well as suggest potential explanations for the unusual disease propensity and disease sparing characteristics of human EOM.
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http://dx.doi.org/10.1007/s40135-017-0141-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669281PMC
September 2017

Effects of retinoic acid signaling on extraocular muscle myogenic precursor cells in vitro.

Exp Cell Res 2017 12 7;361(1):101-111. Epub 2017 Oct 7.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, United States; Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States. Electronic address:

One major difference between limb and extraocular muscles (EOM) is the presence of an enriched population of Pitx2-positive myogenic precursor cells in EOM compared to limb muscle. We hypothesize that retinoic acid regulates Pitx2 expression in EOM myogenic precursor cells and that its effects would differ in leg muscle. The two muscle groups expressed differential retinoic acid receptor (RAR) and retinoid X receptor (RXR) levels. RXR co-localized with the Pitx2-positive cells but not with those expressing Pax7. EOM-derived and LEG-derived EECD34 cells were treated with vehicle, retinoic acid, the RXR agonist bexarotene, the RAR inverse agonist BMS493, or the RXR antagonist UVI 3003. In vitro, fewer EOM-derived EECD34 cells expressed desmin and fused, while more LEG-derived cells expressed desmin and fused when treated with retinoic acid compared to vehicle. Both EOM and LEG-derived EECD34 cells exposed to retinoic acid showed a higher percentage of cells expressing Pitx2 compared to vehicle, supporting the hypothesis that retinoic acid plays a role in maintaining Pitx2 expression. We hypothesize that retinoic acid signaling aids in the maintenance of large numbers of undifferentiated myogenic precursor cells in the EOM, which would be required to maintain EOM normalcy throughout a lifetime of myonuclear turnover.
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http://dx.doi.org/10.1016/j.yexcr.2017.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546114PMC
December 2017

Improvement of Eye Alignment in Adult Strabismic Monkeys by Sustained IGF-1 Treatment.

Invest Ophthalmol Vis Sci 2016 Nov;57(14):6070-6078

Washington National Primate Center and Department of Ophthalmology, University of Washington, Seattle, Washington, United States.

Purpose: The goal of this study was to determine if continuous application of insulin-like growth factor-1 (IGF-1) could improve eye alignment of adult strabismic nonhuman primates and to assess possible mechanisms of effect.

Methods: A continuous release pellet of IGF-1 was placed on one medial rectus muscle in two adult nonhuman primates (M1, M2) rendered exotropic by the alternating monocular occlusion method during the first months of life. Eye alignment and eye movements were recorded for 3 months, after which M1 was euthanized, and the lateral and medial rectus muscles were removed for morphometric analysis of fiber size, nerve, and neuromuscular density.

Results: Monkey 1 showed a 40% reduction in strabismus angle, a reduction of exotropia of approximately 11° to 14° after 3 months. Monkey 2 showed a 15% improvement, with a reduction of its exotropia by approximately 3°. The treated medial rectus muscle of M1 showed increased mean myofiber cross-sectional areas. Increases in myofiber size also were seen in the contralateral medial rectus and lateral rectus muscles. Similarly, nerve density increased in the contralateral medial rectus and yoked lateral rectus.

Conclusions: This study demonstrates that in adult nonhuman primates with a sensory-induced exotropia in infancy, continuous IGF-1 treatment improves eye alignment, resulting in muscle fiber enlargement and altered innervational density that includes the untreated muscles. This supports the view that there is sufficient plasticity in the adult ocular motor system to allow continuous IGF-1 treatment over months to produce improvement in eye alignment in early-onset strabismus.
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http://dx.doi.org/10.1167/iovs.16-19739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114034PMC
November 2016

Prolongation of Relaxation Time in Extraocular Muscles With Brain Derived Neurotrophic Factor in Adult Rabbit.

Invest Ophthalmol Vis Sci 2016 Oct;57(13):5834-5842

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States.

Purpose: We tested the hypothesis that short-term treatment with brain derived neurotrophic factor (BDNF) would alter the contractile characteristics of rabbit extraocular muscle (EOM).

Methods: One week after injections of BDNF in adult rabbit superior rectus muscles, twitch properties were determined in treated and control muscles in vitro. Muscles were also examined for changes in mean cross-sectional areas, neuromuscular junction size, and percent of myofibers expressing specific myosin heavy chain isoforms, and sarcoendoplasmic reticulum calcium ATPases (SERCA) 1 and 2.

Results: Brain derived neurotrophic factor-treated muscles had prolonged relaxation times compared with control muscles. Time to 50% relaxation, time to 100% relaxation, and maximum rate of relaxation were increased by 24%, 27%, and 25%, respectively. No significant differences were seen in time to peak force, twitch force, or maximum rate of contraction. Brain derived neurotrophic factor treatment significantly increased mean cross-sectional areas of slow twitch and tonic myofibers, with increased areas ranging from 54% to 146%. Brain derived neurotrophic factor also resulted in an increased percentage of slow twitch myofibers in the orbital layers, ranging from 54% to 77%, and slow-tonic myofibers, ranging from 44% to 62%. No significant changes were seen SERCA1 or 2 expression or in neuromuscular junction size.

Conclusions: Short-term treatment with BDNF significantly prolonged the duration and rate of relaxation time and increased expression of both slow-twitch and slow-tonic myosin-expressing myofibers without changes in neuromuscular junctions or SERCA expression. The changes induced by BDNF treatment might have potential therapeutic value in dampening/reducing uncontrolled eye oscillations in nystagmus.
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http://dx.doi.org/10.1167/iovs.16-19679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096416PMC
October 2016

A novel explanation of corneal clouding in a bone marrow transplant-treated patient with Hurler syndrome.

Exp Eye Res 2016 07 26;148:83-89. Epub 2016 May 26.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA. Electronic address:

One common complication of mucopolysaccharidosis I-Hurler (MPS1-H) is corneal clouding, which occurs despite current treatments, including bone marrow transplantation. Human corneas were obtained from a 14 year old subject with MPS1-H and visual disability from progressive corneal clouding despite a prior bone marrow transplant at age 2. This was compared to a cornea from a 17 year old donated to our eye bank after his accidental death. The corneas were analyzed microscopically after staining with Alcian blue, antibodies to collagen I, IV, VI, and α-smooth muscle actin. Differences in levels of expression of the indicated molecules were assessed. Corneas from Hurler and control mice were examined similarly to determine potential mechanistic overlap. The MPS1-H subject cornea showed elevations in mucopolysaccharide deposition. The MPS1-H and Hurler mice corneas showed increased and disorganized expression of collagen I and IV relative to the control corneas. The MPS1-H corneas also showed increased and disordered expression of collagen VI. Positive expression of α-smooth muscle actin indicated myofibroblast conversion within the MPS1-H cornea in both the patient and mutant mouse material compared to normal human and control mouse cornea. Increased deposition of collagens and smooth muscle actin correlate with corneal clouding, providing a potential mechanism for corneal clouding despite bone marrow transplantation in MPS1-H patients. It might be possible to prevent or slow the onset of corneal clouding by treating the cornea with drugs known to prevent myofibroblast conversion.
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http://dx.doi.org/10.1016/j.exer.2016.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144536PMC
July 2016

Abnormally Small Neuromuscular Junctions in the Extraocular Muscles From Subjects With Idiopathic Nystagmus and Nystagmus Associated With Albinism.

Invest Ophthalmol Vis Sci 2016 Apr;57(4):1912-20

The University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, Leicester, United Kingdom.

Purpose: Infantile nystagmus syndrome (INS) is often associated with abnormalities of axonal outgrowth and connectivity. To determine if this manifests in extraocular muscle innervation, specimens from children with idiopathic INS or INS and albinism were examined and compared to normal age-matched control extraocular muscles.

Methods: Extraocular muscles removed during normal surgery on children with idiopathic INS or INS and albinism were immunostained for neuromuscular junctions, myofiber type, the immature form of the acetylcholine receptor, and brain-derived neurotrophic factor (BDNF) and compared to age-matched controls.

Results: Muscles from both the idiopathic INS and INS and albinism groups had neuromuscular junctions that were 35% to 71% smaller based on myofiber area and myofiber perimeter than found in age-matched controls, and this was seen on both fast and slow myosin heavy chain isoform-expressing myofibers (all P < 0.015). Muscles from subjects with INS and albinism showed a 7-fold increase in neuromuscular junction numbers on fast myofibers expressing the immature gamma subunit of the acetylcholine receptor. The extraocular muscles from both INS subgroups showed a significant increase in the number and size of slow myofibers compared to age-matched controls. Brain-derived neurotrophic factor was expressed in control muscle but was virtually absent in the INS muscles.

Conclusions: These studies suggest that, relative to the final common pathway, INS is not the same between different patient etiologies. It should be possible to modulate these final common pathway abnormalities, via exogenous application of appropriate drugs, with the hope that this type of treatment may reduce the involuntary oscillatory movements in these children.
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http://dx.doi.org/10.1167/iovs.16-19129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849883PMC
April 2016

Sparing of the extraocular muscles in mdx mice with absent or reduced utrophin expression: A life span analysis.

Neuromuscul Disord 2015 Nov 6;25(11):873-87. Epub 2015 Sep 6.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA; Graduate Program in Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA. Electronic address:

Sparing of the extraocular muscles in muscular dystrophy is controversial. To address the potential role of utrophin in this sparing, mdx:utrophin(+/-) and mdx:utrophin(-/-) mice were examined for changes in myofiber size, central nucleation, and Pax7-positive and MyoD-positive cell density at intervals over their life span. Known to be spared in the mdx mouse, and contrary to previous reports, the extraocular muscles from both the mdx:utrophin(+/-) and mdx:utrophin(-/-) mice were also morphologically spared. In the mdx:utrophin(+/)(-) mice, which have a normal life span compared to the mdx:utrophin(-/-) mice, the myofibers were larger at 3 and 12 months than the wild type age-matched eye muscles. While there was a significant increase in central nucleation in the extraocular muscles from all mdx:utrophin(+/)(-) mice, the levels were still very low compared to age-matched limb skeletal muscles. Pax7- and MyoD-positive myogenic precursor cell populations were retained and were similar to age-matched wild type controls. These results support the hypothesis that utrophin is not involved in extraocular muscle sparing in these genotypes. In addition, it appears that these muscles retain the myogenic precursors that would allow them to maintain their regenerative capacity and normal morphology over a lifetime even in these more severe models of muscular dystrophy.
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http://dx.doi.org/10.1016/j.nmd.2015.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630113PMC
November 2015

Adaptability of the Immature Ocular Motor Control System: Unilateral IGF-1 Medial Rectus Treatment.

Invest Ophthalmol Vis Sci 2015 Jun;56(6):3484-96

Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States 2Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States.

Purpose: Unilateral treatment with sustained release IGF-1 to one medial rectus muscle in infant monkeys was performed to test the hypothesis that strabismus would develop as a result of changes in extraocular muscles during the critical period of development of binocularity.

Methods: Sustained release IGF-1 pellets were implanted unilaterally on one medial rectus muscle in normal infant monkeys during the first 2 weeks of life. Eye position was monitored using standard photographic methods. After 3 months of treatment, myofiber and neuromuscular size, myosin composition, and innervation density were quantified in all rectus muscles and compared to those in age-matched controls.

Results: Sustained unilateral IGF-1 treatments resulted in strabismus for all treated subjects; 3 of the 4 subjects had a clinically significant strabismus of more than 10°. Both the treated medial rectus and the untreated ipsilateral antagonist lateral rectus muscles had significantly larger myofibers. No adaptation in myofiber size occurred in the contralateral functionally yoked lateral rectus or in myosin composition, neuromuscular junction size, or nerve density.

Conclusions: Sustained unilateral IGF-1 treatment to extraocular muscles during the sensitive period of development of orthotropic eye alignment and binocularity was sufficient to disturb ocular motor development, resulting in strabismus in infant monkeys. This could be due to altering fusion of gaze during the early sensitive period. Serial measurements of eye alignment suggested the IGF-1-treated infants received insufficient coordinated binocular experience, preventing the establishment of normal eye alignment. Our results uniquely suggest that abnormal signaling by the extraocular muscles may be a cause of strabismus.
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http://dx.doi.org/10.1167/iovs.15-16761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463801PMC
June 2015

Adaptation of slow myofibers: the effect of sustained BDNF treatment of extraocular muscles in infant nonhuman primates.

Invest Ophthalmol Vis Sci 2015 Jun;56(6):3467-83

Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States 2Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States.

Purpose: We evaluated promising new treatment options for strabismus. Neurotrophic factors have emerged as a potential treatment for oculomotor disorders because of diverse roles in signaling to muscles and motor neurons. Unilateral treatment with sustained release brain-derived neurotrophic factor (BDNF) to a single lateral rectus muscle in infant monkeys was performed to test the hypothesis that strabismus would develop in correlation with extraocular muscle (EOM) changes during the critical period for development of binocularity.

Methods: The lateral rectus muscles of one eye in two infant macaques were treated with sustained delivery of BDNF for 3 months. Eye alignment was assessed using standard photographic methods. Muscle specimens were analyzed to examine the effects of BDNF on the density, morphology, and size of neuromuscular junctions, as well as myofiber size. Counts were compared to age-matched controls.

Results: No change in eye alignment occurred with BDNF treatment. Compared to control muscle, neuromuscular junctions on myofibers expressing slow myosins had a larger area. Myofibers expressing slow myosin had larger diameters, and the percentage of myofibers expressing slow myosins increased in the proximal end of the muscle. Expression of BDNF was examined in control EOM, and observed to have strongest immunoreactivity outside the endplate zone.

Conclusions: We hypothesize that the oculomotor system adapted to sustained BDNF treatment to preserve normal alignment. Our results suggest that BDNF treatment preferentially altered myofibers expressing slow myosins. This implicates BDNF signaling as influencing the slow twitch properties of EOM.
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http://dx.doi.org/10.1167/iovs.15-16852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464045PMC
June 2015

Disease course in mdx:utrophin+/- mice: comparison of three mouse models of Duchenne muscular dystrophy.

Physiol Rep 2015 Apr;3(4)

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota Graduate Program in Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis Minnesota Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota

The mdx mouse model of Duchenne muscular dystrophy (DMD) is used to study disease mechanisms and potential treatments, but its pathology is less severe than DMD patients. Other mouse models were developed to more closely mimic the human disease based on knowledge that upregulation of utrophin has a protective effect in mdx muscle. An mdx:utrophin(-/-) (dko) mouse was created, which had a severe disease phenotype and a shortened life span. An mdx:utrophin(+/-) mouse was also created, which had an intermediate disease phenotype compared to the mdx and dko mice. To determine the usefulness of mdx:utrophin(+/-) mice for long-term DMD studies, limb muscle pathology and function were assessed across the life span of wild-type, mdx, mdx:utrophin(+/-), and dko mice. Muscle function assessment, specifically grip duration and rotarod performance, demonstrated that mdx:utrophin(+/-) mice were weaker for a longer time than mdx mice. Mean myofiber area was smaller in mdx:utrophin(+/-) mice compared to mdx mice at 12 months. Mdx:utrophin(+/-) mice had a higher percentage of centrally nucleated myofibers compared to mdx mice at 6 and 12 months. Collagen I and IV density was significantly higher in mdx:utrophin(+/-) muscle compared to mdx at most ages examined. Generally, mdx:utrophin(+/-) mice showed an intermediate disease phenotype over a longer time course compared to the mdx and dko mice. While they do not genetically mirror human DMD, mdx:utrophin(+/-) mice may be a more useful animal model than mdx or dko mice for investigating long-term efficacy of potential treatments when fibrosis or muscle function is the focus.
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http://dx.doi.org/10.14814/phy2.12391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425985PMC
April 2015

C57BL/6 life span study: age-related declines in muscle power production and contractile velocity.

Age (Dordr) 2015 Jun 17;37(3):9773. Epub 2015 Apr 17.

Program in Physical Therapy, Department of Physical Medicine and Rehabilitation, University of Minnesota Medical School, Rm 366A Children's Rehab Center, 426 Church Street SE, Minneapolis, MN, 55455, USA,

Quantification of key outcome measures in animal models of aging is an important step preceding intervention testing. One such measurement, skeletal muscle power generation (force * velocity), is critical for dynamic movement. Prior research focused on maximum power (P max), which occurs around 30-40 % of maximum load. However, movement occurs over the entire load range. Thus, the primary purpose of this study was to determine the effect of age on power generation during concentric contractions in the extensor digitorum longus (EDL) and soleus muscles over the load range from 10 to 90 % of peak isometric tetanic force (P 0). Adult, old, and elderly male C57BL/6 mice were examined for contractile function (6-7 months old, 100 % survival; ~24 months, 75 %; and ~28 months, <50 %, respectively). Mice at other ages (5-32 months) were also tested for regression modeling. We hypothesized and found that power decreased with age not only at P max but also over the load range. Importantly, we found greater age-associated deficits in both power and velocity when the muscles were contracting concentrically against heavy loads (>50 % P 0). The shape of the force-velocity curve also changed with age (a/P 0 increased). In addition, there were prolonged contraction times to maximum force and shifts in the distribution of the myosin light and heavy chain isoforms in the EDL. The results demonstrate that age-associated difficulty in movement during challenging tasks is likely due, in addition to overall reduced force output, to an accelerated deterioration of power production and contractile velocity under heavily loaded conditions.
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http://dx.doi.org/10.1007/s11357-015-9773-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401475PMC
June 2015

Abnormal activity of neurons in abducens nucleus of strabismic monkeys.

Invest Ophthalmol Vis Sci 2014 Nov 20;56(1):10-9. Epub 2014 Nov 20.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States.

Purpose: Infantile strabismus is characterized by persistent misalignment of the eyes. Mounting evidence suggests that the disorder is associated with abnormalities at the neural level, but few details are known. This study investigated the signals carried by abducens neurons in monkeys with experimentally induced strabismus. We wanted to know whether the firing rates of individual neurons are exclusively related to the position and velocity of one eye and whether the overall level of activity of the abducens nucleus was in the normal range.

Methods: We recorded 58 neurons in right and left abducens nuclei while strabismic monkeys (one esotrope and one exotrope) performed a saccade task. We analyzed the firing rates associated with static horizontal eye position and saccades by fitting the data with a dynamic equation that included position and velocity terms for each eye. Results were compared to previously published data in normal monkeys.

Results: For both strabismic monkeys the overall tonic activity was 50 to 100 spikes/s lower, for every suprathreshold eye position, than what has previously been reported for normal monkeys. This was mostly the result of lower baseline activity; the slopes of rate-position curves were similar to those in previous reports in normal monkeys. The saccade velocity sensitivities were similar to those of normal monkeys, 0.35 for the esotrope and 0.40 for the exotrope. For most neurons the firing rate was more closely related to the position and velocity of the ipsilateral eye.

Conclusions: These data suggest that strabismus can be associated with reduced neural activity in the abducens nucleus.
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http://dx.doi.org/10.1167/iovs.14-15360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283474PMC
November 2014

Wnt and extraocular muscle sparing in amyotrophic lateral sclerosis.

Invest Ophthalmol Vis Sci 2014 Aug 14;55(9):5482-96. Epub 2014 Aug 14.

Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.

Purpose: The extraocular muscles (EOM) and their motor neurons are spared in amyotrophic lateral sclerosis (ALS). In limb muscle, axon retraction from the neuromuscular junctions occurs early in the disease. Wnts, a conserved family of secreted signaling molecules, play a critical role in neuromuscular junction formation. This is the first study to examine Wnt signaling for its potential involvement in maintenance of normal morphology in EOM in ALS.

Methods: Extraocular muscle and limb muscle axons, neuromuscular junctions, and myofibers from control, aging, and ALS subjects and the SOD1(G93A) mouse model of ALS were quantified for their expression of Wnt1, Wnt3a, Wnt5a, Wnt7a, and β-catenin.

Results: All four Wnt isoforms were expressed in most axon profiles in all human EOM. Significantly fewer were positive for Wnt1, Wnt3a, and Wnt7a in the human limb muscles. Similar differential patterns in Wnt myofiber expression were also seen except in the case of Wnt7a, where expression was elevated. In the SOD1(G93A) mouse, all four Wnt isoforms were significantly decreased in the neuromuscular junctions at the terminal stage compared to values in age-matched controls. β-Catenin was activated in a subset of myofibers in EOM and limb muscle in all subjects.

Conclusions: The differences in expression of Wnts in EOM and limb muscle, particularly at the neuromuscular junction level, suggest that they play a role in the pathophysiology of ALS. Collectively, the data support a role for signaling of Wnts in the preservation of the EOM in ALS and their dysregulation and the subsequent development of pathology in the ALS limb muscles.
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http://dx.doi.org/10.1167/iovs.14-14886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580151PMC
August 2014

Dystrophic changes in extraocular muscles after gamma irradiation in mdx:utrophin(+/-) mice.

PLoS One 2014 21;9(1):e86424. Epub 2014 Jan 21.

Department of Ophthalmology and Visual Neurosciences, and Graduate Program in Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, Minnesota, United States of America.

Extraocular muscles (EOM) have a strikingly different disease profile than limb skeletal muscles. It has long been known that they are spared in Duchenne (DMD) and other forms of muscular dystrophy. Despite many studies, the cause for this sparing is not understood. We have proposed that differences in myogenic precursor cell properties in EOM maintain normal morphology over the lifetime of individuals with DMD due to either greater proliferative potential or greater resistance to injury. This hypothesis was tested by exposing wild type and mdx:utrophin(+/-) (het) mouse EOM and limb skeletal muscles to 18 Gy gamma irradiation, a dose known to inhibit satellite cell proliferation in limb muscles. As expected, over time het limb skeletal muscles displayed reduced central nucleation mirrored by a reduction in Pax7-positive cells, demonstrating a significant loss in regenerative potential. In contrast, in the first month post-irradiation in the het EOM, myofiber cross-sectional areas first decreased, then increased, but ultimately returned to normal compared to non-irradiated het EOM. Central nucleation significantly increased in the first post-irradiation month, resembling the dystrophic limb phenotype. This correlated with decreased EECD34 stem cells and a concomitant increase and subsequent return to normalcy of both Pax7 and Pitx2-positive cell density. By two months, normal het EOM morphology returned. It appears that irradiation disrupts the normal method of EOM remodeling, which react paradoxically to produce increased numbers of myogenic precursor cells. This suggests that the EOM contain myogenic precursor cell types resistant to 18 Gy gamma irradiation, allowing return to normal morphology 2 months post-irradiation. This supports our hypothesis that ongoing proliferation of specialized regenerative populations in the het EOM actively maintains normal EOM morphology in DMD. Ongoing studies are working to define the differences in the myogenic precursor cells in EOM as well as the cellular milieu in which they reside.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086424PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897728PMC
September 2014

Postulating a role for connective tissue elements in inferior oblique muscle overaction (an American Ophthalmological Society thesis).

Trans Am Ophthalmol Soc 2013 Sep;111:119-32

Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, and Pediatric Ophthalmology & Adult Strabismus, PA, Plano, Texas (Dr Stager); Departments of Ophthalmology and Visual Neurosciences, and Department of Neuroscience, University of Minnesota, Minneapolis (Dr McLoon); and the Retina Foundation of the Southwest, Dallas, Texas, and Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas (Dr Felius).

Purpose: To compare the localization and density of collagens I, IV, VI, and elastin, the major protein components of connective tissue, in the inferior oblique muscle of patients with overelevation in adduction and in controls and to characterize changes that develop following surgery. Biomechanical studies suggest that the connective tissue matrix plays a critical role in extraocular muscle function, determining tensile strength and force transmission during contraction.

Methods: Prospective laboratory-based case-control study of inferior oblique muscle specimens from 31 subjects: 16 with primary inferior oblique overaction, 6 with craniofacial dysostosis, and 9 normal controls. Collagen I, IV, VI, and elastin were localized and quantified using immunohistochemical staining. Densities were compared using analysis of variance and post hoc comparisons.

Results: In primary inferior oblique overaction, all connective tissue components in unoperated specimens were elevated compared to controls (P<.0001). Previously operated muscles showed normal levels of collagens IV and VI (P>.27) but increased collagen I. In unoperated craniofacial dysostosis specimens, only elastin was elevated (P=.03), whereas density of collagens IV and VI was lower in previously operated vs unoperated specimens (P=.015).

Conclusions: Elevated collagen and elastin levels in the cohort with primary inferior oblique overaction are consistent with the clinical finding of muscle stiffness. Contrarily, normal connective tissue densities in craniofacial dysostosis support the hypothesis that overelevation in this group reflects anomalous muscle vectors rather than tissue changes. Surgical intervention was associated with changes in the connective tissue matrix in both cohorts. These results have ramifications for treating patients with overelevation in adduction.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812716PMC
September 2013

The role of Pitx2 in maintaining the phenotype of myogenic precursor cells in the extraocular muscles.

PLoS One 2013 7;8(3):e58405. Epub 2013 Mar 7.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.

Many differences exist between extraocular muscles (EOM) and non-cranial skeletal muscles. One striking difference is the sparing of EOM in various muscular dystrophies compared to non-cranial skeletal muscles. EOM undergo continuous myonuclear remodeling in normal, uninjured adults, and distinct transcription factors are required for the early determination, development, and maintenance of EOM compared to limb skeletal muscle. Pitx2, a bicoid-like homeobox transcription factor, is required for the development of EOM and the maintenance of characteristic properties of the adult EOM phenotype, but is not required for the development of limb muscle. We hypothesize that these unique properties of EOM contribute to the constitutive differences between EOM and non-craniofacial skeletal muscles. Using flow cytometry, CD34(+)/Sca1(-/)CD45(-/)CD31(-) cells (EECD34 cells) were isolated from extraocular and limb skeletal muscle and in vitro, EOM EECD34 cells proliferated faster than limb muscle EECD34 cells. To further define these myogenic precursor cells from EOM and limb skeletal muscle, they were analyzed for their expression of Pitx2. Western blotting and immunohistochemical data demonstrated that EOM express higher levels of Pitx2 than limb muscle, and 80% of the EECD34 cells expressed Pitx2. siRNA knockdown of Pitx2 expression in EECD34 cells in vitro decreased proliferation rates and impaired the ability of EECD34 cells to fuse into multinucleated myotubes. High levels of Pitx2 were retained in dystrophic and aging mouse EOM and the EOM EECD34 cells compared to limb muscle. The differential expression of Pitx2 between EOM and limb skeletal muscle along with the functional changes in response to lower levels of Pitx2 expression in the myogenic precursor cells suggest a role for Pitx2 in the maintenance of constitutive differences between EOM and limb skeletal muscle that may contribute to the sparing of EOM in muscular dystrophies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058405PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591328PMC
September 2013

Effects of sequential injections of hepatocyte growth factor and insulin-like growth factor-I on adult rabbit extraocular muscle.

J AAPOS 2012 Aug;16(4):354-60

Department of Ophthalmology, University of Minnesota, Minneapolis, MN, USA.

Purpose: To determine whether hepatocyte growth factor (HGF) and insulin-like growth factor-I (IGF-I) have synergistic effects in promoting extraocular muscle fiber growth and force generation.

Methods: A superior rectus muscle of adult rabbits was treated with either a single injection of HGF or sequential injections of HGF followed 1 week later by IGF-I. One week after HGF alone and 1 week after the IGF-I injection, the superior rectus muscles from treated and control orbits were examined for alterations in force generation as well as changes in myofiber size.

Results: Injection of HGF alone did not result in changes to muscle force, specific tension, or myofiber cross-sectional area; however, it did result in a significant increase in numbers of satellite cells. Sequential injection of HGF and IGF-I resulted in significantly increased force, specific tension, and myofiber cross-sectional areas as well as increased numbers of satellite cells.

Conclusions: Preinjection with HGF augments the treatment effect of IGF-I. This synergistic effect is likely a result of HGF-induced activation of satellite cells and should allow a reduction in IGF-I dosing required to produce a given increase in extraocular muscle force generation.
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http://dx.doi.org/10.1016/j.jaapos.2012.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431511PMC
August 2012

Extraocular muscles in patients with infantile nystagmus: adaptations at the effector level.

Arch Ophthalmol 2012 Mar;130(3):343-9

Department of Ophthalmology, University of Minnesota, Minneapolis, MN 55455, USA.

Objective: To test the hypothesis that the extraocular muscles (EOMs) of patients with infantile nystagmus have muscular and innervational adaptations that may have a role in the involuntary oscillations of the eyes.

Methods: Specimens of EOMs from 10 patients with infantile nystagmus and postmortem specimens from 10 control subjects were prepared for histologic examination. The following variables were quantified: mean myofiber cross-sectional area, myofiber central nucleation, myelinated nerve density, nerve fiber density, and neuromuscular junction density.

Results: In contrast to control EOMs, infantile nystagmus EOMs had significantly more centrally nucleated myofibers, consistent with cycles of degeneration and regeneration. The EOMs of patients with nystagmus also had a greater degree of heterogeneity in myofiber size than did those of controls, with no difference in mean myofiber cross-sectional area. Mean myelinated nerve density, nerve fiber density, and neuromuscular junction density were also significantly decreased in infantile nystagmus EOMs.

Conclusions: The EOMs of patients with infantile nystagmus displayed a distinct hypoinnervated phenotype. This represents the first quantification of changes in central nucleation and myofiber size heterogeneity, as well as decreased myelinated nerve, nerve fiber, and neuromuscular junction density. These results suggest that deficits in motor innervation are a potential basis for the primary loss of motor control.

Clinical Relevance: Improved understanding of the etiology of nystagmus may direct future diagnostic and treatment strategies.
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http://dx.doi.org/10.1001/archophthalmol.2011.381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759680PMC
March 2012

Effects of the sustained release of IGF-1 on extraocular muscle of the infant non-human primate: adaptations at the effector organ level.

Invest Ophthalmol Vis Sci 2012 Jan 5;53(1):68-75. Epub 2012 Jan 5.

Department of Ophthalmology, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Purpose: The authors have demonstrated that prolonged exposure of adult rabbit extraocular muscle (EOM) to insulin-like growth factor-1 (IGF-1) results in significantly increased cross-sectional area and muscle force generation lasting over 3 months. Here the authors assess the effects on EOM of sustained IGF-1 treatment on normal binocular infant Macaca mulatta.

Methods: Sustained-release IGF-1 pellets were implanted bilaterally in each medial rectus (MR) muscle of two normal infant non-human primates. Eye position was examined using corneal light reflex testing. After 3 months, morphometric analyses of myofiber cross-sectional area and innervation density in treated MR muscles were compared with an age-matched control and with antagonist lateral rectus (LR) muscles.

Results: After 3 months, the slow-release pellets remained at the implantation site in all four MR muscles treated. The treated MR showed pronounced increases in cross-sectional area and nerve density, mirrored in the untreated antagonist LR.

Conclusions: Three months of bilateral sustained IGF-1 release in infant non-human primate MR resulted in increased muscle size and innervation density, mirrored in the untreated antagonist LR. It appears that bilateral MR treatment resulted in slow adaptation of both treated MR and contralateral LR muscles over time such that functional homeostasis and near-normal alignment were maintained. Further work is needed to determine what signaling mechanisms maintain proportional innervation when EOMs are forced to adapt to an externally applied perturbation.
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http://dx.doi.org/10.1167/iovs.11-8356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292383PMC
January 2012