Adaptation of Slow Myofibers: The Effect of Sustained BDNF Treatment of Extraocular Muscles in Infant Nonhuman Primates

Willoughby, Christy L.; Filippi, Jérôme; Walton, Mark M. G.; Mustari, Michael J.; McLoon, Linda K.

doi:10.1167/iovs.15-16852

Cited by 21 publications

(36 citation statements)

References 82 publications

(113 reference statements)

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“…53,54 Unilateral oversupply of exogenous BDNF to a horizontal EOM did not induce strabismus in a primate animal model. 55 In our samples, BDNF gene expression was not significantly changed, while both specific receptors for NGF and BDNF, trkA (NTRK1) and trkB (NTRK2), were upregulated in strabismic muscles (Table 2), consistent with our previous microarray report. 21 …”

Section: Discussionsupporting

confidence: 91%

Altered Protein Composition and Gene Expression in Strabismic Human Extraocular Muscles and Tendons

Agarwal

Feng

Altick

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeTo determine whether structural protein composition and expression of key regulatory genes are altered in strabismic human extraocular muscles.MethodsSamples from strabismic horizontal extraocular muscles were obtained during strabismus surgery and compared with normal muscles from organ donors. We used proteomics, standard and customized PCR arrays, and microarrays to identify changes in major structural proteins and changes in gene expression. We focused on muscle and connective tissue and its control by enzymes, growth factors, and cytokines.ResultsStrabismic muscles showed downregulation of myosins, tropomyosins, troponins, and titin. Expression of collagens and regulators of collagen synthesis and degradation, the collagenase matrix metalloproteinase (MMP)2 and its inhibitors, tissue inhibitor of metalloproteinase (TIMP)1 and TIMP2, was upregulated, along with tumor necrosis factor (TNF), TNF receptors, and connective tissue growth factor (CTGF), as well as proteoglycans. Growth factors controlling extracellular matrix (ECM) were also upregulated. Among 410 signaling genes examined by PCR arrays, molecules with downregulation in the strabismic phenotype included GDNF, NRG1, and PAX7; CTGF, CXCR4, NPY1R, TNF, NTRK1, and NTRK2 were upregulated. Signaling molecules known to control extraocular muscle plasticity were predominantly expressed in the tendon rather than the muscle component. The two horizontal muscles, medial and lateral rectus, displayed similar changes in protein and gene expression, and no obvious effect of age.ConclusionsQuantification of proteins and gene expression showed significant differences in the composition of extraocular muscles of strabismic patients with respect to important motor proteins, elements of the ECM, and connective tissue. Therefore, our study supports the emerging view that the molecular composition of strabismic muscles is substantially altered.

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Section: Discussionsupporting

confidence: 91%

Altered Protein Composition and Gene Expression in Strabismic Human Extraocular Muscles and Tendons

Agarwal

Feng

Altick

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…We recently showed that both BDNF and tropomyosin receptor kinase B (trkB), the receptor for BDNF, are expressed in adult EOM. 7 This study sought to determine if exogenous treatment with BDNF could alter contraction or relaxation rates in adult rabbit EOM.…”

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confidence: 99%

“…Recent studies demonstrated that insulin-like growth factor-1 (IGF-1) applied unilaterally over a 3 month time-period to infant monkey medial rectus muscle resulted in development of strabismus, 8 while BDNF treatment did not. 7 However, analysis of the effects of sustained release of BDNF showed that there was a significant effect on the myofibers that expressed the slow myosin heavy chain isoform (MyHC). Not only were these BDNF-treated myofibers significantly larger than age-matched control slow myofibers after the 3 months of continuous BDNF exposure, there was also an increased number of slow-positive myofibers in these BDNF-treated infant extraocular muscles.…”

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confidence: 99%

“…This suggests that the BDNF had an effect on fiber type switching. 7 Additionally, the neuromuscular junctions on the slow myofibers were also proportionally enlarged. These studies support the view that growth factors can significantly influence fiber type characteristics and function.…”

mentioning

confidence: 99%

“…Length and area of neuromuscular junctions were also determined, as previous studies suggested that neuromuscular junction size may change in response to BDNF treatment. 7 …”

mentioning

confidence: 99%

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

Nelson

Stevens

McLoon

2016

Invest. Ophthalmol. Vis. Sci.

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PurposeWe tested the hypothesis that short-term treatment with brain derived neurotrophic factor (BDNF) would alter the contractile characteristics of rabbit extraocular muscle (EOM).MethodsOne 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.ResultsBrain 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.ConclusionsShort-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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Extraocular Muscle Repair and Regeneration

Verma

Fitzpatrick

McLoon

2017

Curr Ophthalmol Rep

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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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Adaptation of Slow Myofibers: The Effect of Sustained BDNF Treatment of Extraocular Muscles in Infant Nonhuman Primates

Abstract: 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.

Cited by 21 publications

References 82 publications

Altered Protein Composition and Gene Expression in Strabismic Human Extraocular Muscles and Tendons

Altered Protein Composition and Gene Expression in Strabismic Human Extraocular Muscles and Tendons

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

Extraocular Muscle Repair and Regeneration

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