Extraocular Muscle Repair and Regeneration

Verma, Mayank; Fitzpatrick, Krysta R.; McLoon, Linda K.

doi:10.1007/s40135-017-0141-4

Cited by 36 publications

(51 citation statements)

References 81 publications

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“…One potential explanation for the increased cross-sectional area of the GDNF-treated muscles is that GDNF might foster a proliferative response in the muscle regenerative populations. Pax7 is a transcription factor expressed on quiescent satellite cells in all skeletal muscles and plays an important role in skeletal muscle growth, repair, and regeneration [ 25 , 26 ], with elevated levels in extraocular muscles [ 27 ]. Analysis showed that there were no significant differences in the number of Pax7-positive satellite cells per myofiber number between any of the areas or regions ( Fig 8 ).…”

Section: Resultsmentioning

confidence: 99%

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

Fitzpatrick¹,

Cucak²,

McLoon³

2018

PLoS ONE

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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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Section: Resultsmentioning

confidence: 99%

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

Fitzpatrick¹,

Cucak²,

McLoon³

2018

PLoS ONE

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“…Here, we aimed to investigate if there were intrinsic trophic differences between muscle progenitors derived from the EOMs, the muscles of the tongue, the buccinator and the EDL, that could explain why the EOMs SCs show higher proliferative and fusion rates (reviewed by [44]), features that seem to be responsible for the extraordinary EOMs regenerative properties and their resistance to certain diseases [11,13].…”

Section: Discussionmentioning

confidence: 99%

Muscle Progenitors Derived from Extraocular Muscles Express Higher Levels of Neurotrophins and their Receptors than other Cranial and Limb Muscles

Carrero-Rojas

Benítez‐Temiño

Pastor

et al. 2020

Cells

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Extraocular muscles (EOMs) show resistance to muscle dystrophies and sarcopenia. It has been recently demonstrated that they are endowed with different types of myogenic cells, all of which present an outstanding regenerative potential. Neurotrophins are important modulators of myogenic regeneration and act promoting myoblast proliferation, enhancing myogenic fusion rates and protecting myotubes from inflammatory stimuli. Here, we adapted the pre-plate cell isolation technique to obtain myogenic progenitors from the rat EOMs, and quantified their in vitro expression of neurotrophins and their receptors by RT-qPCR and immunohistochemistry, respectively. The results were compared with the expression on progenitors isolated from buccinator, tongue and limb muscles. Our quantitative analysis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) transcripts showed, for the first time, that EOMs-derived cells express more of these factors and that they expressed TrkA, but not TrkB and TrkC receptors. On the contrary, the immunofluorescence analysis demonstrated high expression of p75 NTR on all myogenic progenitors, with the EOMs-derived cells showing higher expression. Taken together, these results suggest that the intrinsic trophic differences between EOMs-derived myogenic progenitors and their counterparts from other muscles could explain why those cells show higher proliferative and fusion rates, as well as better regenerative properties.

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“…However, due to the relative inaccessibility of EOMs we have used biopsies of orbicularis oculi muscle (OOM) as a surrogate orbital muscle to pro le transcripts which may closely resemble the EOM transcriptome. As craniofacial muscles both EOMs and OOMs share similar embryological origins and many of the anatomical, physiological and molecular characteristics which distinguish EOMs from skeletal limb muscle [12]. Both EOMs and OOMs have fast ring rates [13], high mitochondrial content and oxidative capacities [14,15] and type II bre predominance [9,12].…”

Section: Introductionmentioning

confidence: 99%

“…As craniofacial muscles both EOMs and OOMs share similar embryological origins and many of the anatomical, physiological and molecular characteristics which distinguish EOMs from skeletal limb muscle [12]. Both EOMs and OOMs have fast ring rates [13], high mitochondrial content and oxidative capacities [14,15] and type II bre predominance [9,12]. Therefore, the use of OOMs as a surrogate for EOM will provide important validation of gene expression tissue-speci city of the craniofacial myotome in OP-MG vs normal controls.…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiling of Orbital Muscles in Treatment-Resistant Ophthalmoplegic Myasthenia Gravis

Europa

Nel

Heckmann

2020

Preprint

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Background: Unbiased in silico approaches applied to genome-wide data prioritized putative functional gene variants associating with treatment-resistant ophthalmoplegic myasthenia gravis (OP-MG). Although altered expression of genes harbouring these variants, or associated pathways, were shown in patient-derived myocyte models, gene expression in orbital-derived muscle was required to test the validity of the predictions. Methods: We sampled orbicularis oculi muscle (OOM) and one paralysed extraocular muscle (EOM) from six individuals with OP-MG during blepharoptosis and re-alignment surgeries, respectively. For controls, the OOMs were sampled from four individuals without myasthenia undergoing surgery for non-muscle causes of ptosis, and one non-paralysed EOM. Using a qPCR array, expression of 120 genes was compared between OP-MG and control OOMs, profiling putative “OP-MG” genes, genes in related biological pathways and genes reported to be dysregulated in MG cases or experimental MG models, and in EOMs of cases with strabismus. Normalization was performed with two stable reference genes. Differential gene expression was compared between OP-MG and control samples using the ΔΔCT method. Co-expression was analysed by pairwise correlation of gene transcripts to infer expression networks. Results: Overall, transcript levels were similar in OOMs and EOMs (p=0.72). In OOMs, significant downregulated expression of eight genes was observed in OP-MG cases compared with controls (>2-fold; p≤0.016), including TFAM, a mitochondrial transcription factor, and genes related to the following pathways: atrophy signalling; muscle regeneration and contraction; glycogen synthesis; and extracellular matrix remodelling. Several microRNAs, known to be highly expressed in EOMs, are predicted to regulate some of these genes. Co-expression analyses of gene-pairs suggested high interconnectedness of gene expression networks in OP-MG muscle, but not controls (r>0.96, p<0.01). Significant inverse directions of gene-pair correlations were noted in OP-MG vs controls OOM networks (r≥0.92, p<0.001) involving most OP-MG genes overlapping prominently with muscle atrophy/contractility and oxidative metabolism genes. Conclusions: The gene expression in orbital muscles derived from OP-MG individuals compared with normal controls, support the pathogenic hypothesis previously generated from whole genome sequence analyses. Repression of gene transcripts in OP-MG orbital muscle implicate tissue-specific regulatory mechanisms, which may inform future biomarker discovery approaches.

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Extraocular Muscle Repair and Regeneration

Cited by 36 publications

References 81 publications

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

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

Muscle Progenitors Derived from Extraocular Muscles Express Higher Levels of Neurotrophins and their Receptors than other Cranial and Limb Muscles

Gene Expression Profiling of Orbital Muscles in Treatment-Resistant Ophthalmoplegic Myasthenia Gravis

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