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

Fitzpatrick, Krysta R.; Cucak, Anja; McLoon, Linda K.

doi:10.1371/journal.pone.0202861

Cited by 5 publications

(10 citation statements)

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“…Combined, these data suggest that endogenous and potentially dysregulated GDNF expression may be involved in the molecular control in the development and/or maintenance of eye misalignment in early life. Muscle force was significantly reduced after one month of sustained GDNF treatment of adult rabbit extraocular muscles 5 . Mean twitch contraction times were significantly increased compared to naïve control muscles in the treated muscles, which would result in a more sustained, albeit weaker, tension in the treated muscles 5 .…”

Section: Discussionmentioning

confidence: 92%

“…Muscle force was significantly reduced after one month of sustained GDNF treatment of adult rabbit extraocular muscles 5 . Mean twitch contraction times were significantly increased compared to naïve control muscles in the treated muscles, which would result in a more sustained, albeit weaker, tension in the treated muscles 5 . In young chick extraocular muscles, GDNF injection decreased contraction duration 11 .…”

Section: Discussionmentioning

confidence: 92%

“…The polyinnervated neuromuscular junctions in the GDNF over-expressing mouse muscles were electrophysiologically weak 60 . This is interesting in light of the decreased force generation in GDNF-treated rabbit extraocular muscles 5 . Further work is needed to assess functional and protein changes specifically at the neuromuscular junctions after GDNF treatment.…”

Section: Discussionmentioning

confidence: 95%

“…These included decreased levels of glial cell line-derived neurotrophic factor (GDNF) compared to levels in age-matched control extraocular muscles 1 , 2 . This was interesting in light of previous studies which demonstrated that orbital injection of GDNF in juvenile chicks or sustained GDNF treatment of a single extraocular muscle in adult rabbits resulted in altered muscle force generation 3 – 5 . These studies suggest that modulating the levels of GDNF in selected extraocular muscles may improve eye alignment in individuals with strabismus, and conversely that modulating GDNF levels during early life has the potential to produce a strabismus.…”

Section: Introductionmentioning

confidence: 95%

“…Based on the demonstration that GDNF levels were altered in the muscles from surgical sample from individuals with strabismus, as shown by using both DNA microarray and RNA PCR analyses 1 , 2 , sustained treatment of rabbits with GDNF was performed and resulted in muscles that generated decreased force compared to age-matched controls 5 . Based on these results, in the present study we tested the effect of unilateral sustained delivery of GDNF to one medial rectus muscle in six infant monkeys.…”

Section: Introductionmentioning

confidence: 99%

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

Filippi

Willoughby

Kueppers

et al. 2020

Sci Rep

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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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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Filippi

Willoughby

Kueppers

et al. 2020

Sci Rep

Self Cite

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Flavonoids Sophoranone Promotes Differentiation of C2C12 and Extraocular Muscle Satellite Cells

et al. 2020

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Introduction: Paralytic strabismus involves a functional loss of extraocular muscles resulting from muscular or neuronal disorders. Currently, only a limited number of drugs are available for functional repair of extraocular muscles. Here, we investigated the effects of a novel drug, flavonoids sophoranone, on the differentiation of extraocular muscles as assessed in bothin vivo and in vitro models. Materials and Methods: The effect of flavonoids sophoranone on C2C12 cells was examinedin vitro as evaluated with use of apoptosis, reactive oxygen species (ROS), and cell viability assays. Then, both in vivo and in vitro effects of this drug were examined on the differentiation of C2C12 and satellite cells within extraocular muscles in rabbits. For these latter experiments, RT-PCR and Western blot assays were used to determine expression levels of markers for myogenic differentiation. Results: With use of flavonoids sophoranone concentrations ranging from 0 to 10 μM, no effects were observed upon cell apoptosis, ROS, and cell cycle in C2C12 cells. Based on MTT assay results, flavonoids sophoranone was shown to increase C2C12 cell proliferation. Moreover, flavonoids sophoranone promoted the differentiation of C2C12 and satellite cells within extraocular muscles in rabbits, which were verified as based on cell morphology and expression levels of mRNA and protein markers of myogenic differentiation. Finally, flavonoids sophoranone treatment also increased gene expressions of Myh3, Myog, and MCK. Conclusion: The capacity for flavonoids sophoranone to upgrade the differentiation of both C2C12 and satellite cells within extraocular muscles in rabbits at concentrations producing no adverse effects suggest that this drug may provide a safe and effective means to promote repair of damaged extraocular muscles.

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Effect of Fibroblast Growth Factor 2 on Extraocular Muscle Structure and Function

Rudell

McLoon

2021

Invest. Ophthalmol. Vis. Sci.

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Purpose Mutations in the fibroblast growth factor (FGF) receptor can result in strabismus, but little is known about how FGFs affect extraocular muscle structure and function. These were assessed after short-term and long-term exposure to exogenously applied FGF2 to determine the effect of enhanced signaling. Methods One superior rectus muscle of adult rabbits received either a series of three injections of 500 ng, 1 µg, or 5 µg FGF2 and examined after 1 week, or received sustained treatment with FGF2 and examined after 1, 2, or 3 months. Muscles were assessed for alterations in force generation, myofiber size, and satellite cell number after each treatment. Results One week after the 5 µg FGF2 injections, treated muscles showed significantly increased force generation compared with naïve controls, which correlated with increased myofiber cross-sectional areas and Pax7-positive satellite cells. In contrast, 3 months of sustained FGF2 treatment resulted in decreased force generation, which correlated with decreased myofiber size and decreased satellite cells compared with naïve control and the untreated contralateral side. Conclusions FGF2 had distinctly different effects when short-term and long-term treatments were compared. The decreased size and ability to generate force correlated with decreased myofiber areas seen in individuals with Apert syndrome, where there is sustained activation of FGF signaling. Knowing more about signaling pathways critical for extraocular muscle function, development, and disease will pave the way for improved treatment options for strabismus patients with FGF abnormalities in craniofacial disease, which also may be applicable to other strabismus patients.

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

Cited by 5 publications

References 50 publications

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

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

Flavonoids Sophoranone Promotes Differentiation of C2C12 and Extraocular Muscle Satellite Cells

Effect of Fibroblast Growth Factor 2 on Extraocular Muscle Structure and Function

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