Morphological ciliary muscle changes associated with form deprivation-induced myopia

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Highlights

  • Induced axial myopia in guinea pigs results inciliary muscle morphological changes that differ from human myopia.

  • Induced ciliary muscle changes suggest atrophy or inhibited muscle growth.

  • New guinea pig strains were described for myopia development research.

Abstract

Myopic children have larger ciliary muscles than non-myopic children, suggesting that the ciliary muscle may have an impact on or be affected by refractive error development. The guinea pig represents an attractive model organism for myopia development research. The purpose of the study was to investigate whether form deprivation-induced myopia in one or more strains of guinea pig causes thickening of the ciliary muscle as seen in human myopia. Thirty-nine guinea pigs were bred from in-house progenitors obtained from Cincinnati Children's Hospital (Cincinnati) and the United States Army (Strain 13). At 2–4 days of age the right eyes of animals were exposed to form deprivation for 7 days while the fellow eyes served as controls. Refractive error was determined with retinoscopy while vitreous chamber depth (VCD) and axial length (AL) were determined with A-scan ultrasound. Ciliary muscle characteristics (ciliary muscle length, cross-sectional area, volume, cell number, cell size, and smooth muscle actin concentration) were determined histologically with antibody labeling and analyzed according to whether the animal developed axial myopia (anisometropia > −2.00 D with VCD and/or AL differences > 0.1 mm) or was unresponsive. This analysis method yielded four groups with Group 1 having no induced myopia but with axial elongation (n = 11), Group 2 having myopia without vitreous or axial elongation (n = 8), Group 3 having myopia with either vitreous or axial elongation (n = 11), and Group 4 having myopia with both vitreous and axial elongation (n = 8). There were no post-treatment inter-ocular differences between strains or for the overall group of animals for any ciliary muscle variable; however, a higher response group number in multivariate ordinal regression was related to having a treated compared to fellow eye that had a lower smooth muscle actin concentration (p = 0.006), with a shorter ciliary muscle length (p = 0.042), and a less oblate eye shape (p = 0.010). Guinea pig ciliary muscle length and smooth muscle actin concentration were significantly less in the treated eyes of axially myopic animals suggesting that 7 days of form deprivation induced ciliary muscle cellular atrophy or inhibited ciliary muscle growth. Form deprivation myopia in the guinea pig does not result in the increase in ciliary muscle thickness associated with human juvenile and adult myopia.

Introduction

The ciliary muscle's link to myopia development has long been suspected. Historically, near work (cumulative accommodative effort) was considered a primary risk factor for myopia development (Zylbermann et al., 1993). However, more recently, the relationship between the risk of myopia onset and near work has been questioned (Huang et al., 2015; Ip et al., 2008; Saw et al., 2006; Zadnik et al., 2015). While near work has lost some favor, the accommodative system is still relevant to myopia development because myopic individuals have increased accommodative lags (Gwiazda et al., 2005; Mutti et al., 2006), higher AC/A ratios (Gwiazda et al., 2005; Mutti et al., 2000), and thicker ciliary muscles/bodies (Bailey et al., 2008; Oliveira et al., 2005; Pucker et al., 2013). Subsequently, these associations have led to the hypothesis that ciliary muscle thickening may play a role in producing the relatively less oblate ocular shape found in myopic eyes, specifically that ciliary muscle thickening may cause equatorial eye restriction resulting in axial elongation without proportional equatorial expansion (Atchison et al., 2005, 2006; Mutti et al., 2007).

A less oblate ocular shape in humans is also associated with a more hyperopic relative peripheral refraction (Atchison et al., 2005, 2006; Mutti et al., 2007), a feature that is currently believed to be a key regulator of myopia development (Aller and Wildsoet, 2013; Anstice and Phillips, 2011; Liu and Wildsoet, 2012; Sankaridurg et al., 2011; Smith et al., 2009; Walline et al., 2013). Foveal visual cues may be important for regulating refractive error development, but the peripheral retina has been shown to guide eye growth without input from the fovea in animal models (Smith et al., 2009). Smith et al. demonstrated that if one ablates a rhesus monkey's fovea, peripheral visual stimuli (form deprivation and minus lenses) are still able to induce axial elongation and myopic refractive error at the fovea (Smith et al., 2007, 2009). The success of treating human peripheral hyperopic defocus with orthokeratology and center-distance bifocal contact lenses reinforces the peripheral visual defocus theory (Aller and Wildsoet, 2013; Anstice and Phillips, 2011; Cho et al., 2005; Sankaridurg et al., 2011; Walline et al., 2009, 2013). Yet the myopia community currently lacks a mechanistic understanding of how a less oblate myopic eye shape is created.

The guinea pig is an attractive animal model for investigating this mechanism because: 1) guinea pigs reach adulthood within about 90 days of life, 2) guinea pigs have the ability to accommodate, 3) untreated guinea pig ciliary muscle volume increases 2.5 fold during their first 90 days of life, and 4) guinea pigs have prominent longitudinal ciliary muscle fibers (region of muscle associated with human myopia) (Howlett and McFadden, 2006, 2007; 2009; Ostrin et al., 2014; Pucker et al., 2014, 2015). However, it is unclear whether induced myopia alters the ciliary muscle growth pattern of guinea pigs, which is a first step toward understanding whether there may be a causal relationship between ciliary thickness and myopia development. Therefore, the purpose of the study was to investigate whether form deprivation-induced myopia in one or more strains of guinea pig causes thickening of the ciliary muscle as seen in human myopia.

Section snippets

Animals

This study utilized Strain 13 guinea pigs (n = 14; Cavia porcellus) that were obtained from the United States Army Medical Research Institute of Infectious Diseases (Fort Detrick, MD) and a guinea pig strain with unknown origins (Cincinnati strain; n = 25) that is currently being maintained by Cincinnati Children's Hospital (Cincinnati, OH). Commercially available guinea pigs from Elm Hill Labs (Chelmsford, MA) were excluded because they are known to be resistant to myopia induction (Jiang et

Biometric measurements

All guinea pigs were able to successfully wear the form-deprivation hoods. The lenses stayed on all hoods, though four of guinea pigs had their hood fall off between one and two times. Hood removal did not result in a discernible link to being responsive to the treatment. There was no substantial variation in the percentages of animals in each response group between the two strains. The Cincinnati guinea pigs were between 50% and 73% of the animals in each of the four response groups, similar

Discussion

An association between thicker human ciliary bodies/muscles and myopic refractive errors in children and adults is well established in the literature, yet the mechanism leading to a thicker ciliary body/muscle is currently unknown, motivating the need to study ciliary muscle development in animal models (Bailey et al., 2008; Oliveira et al., 2005; Pucker et al., 2013). The purpose of the study was to investigate whether form deprivation-induced myopia in one or more strains of guinea pig causes

Acknowledgements

The authors thank the National Eye Institute (K08EY023264; P30EY003039) and the University of Alabama at Birmingham (Investment Pool for Action Funds) for financial and equipment support during this experiment. The authors also thank the United States Army Medical Research Institute of Infectious Diseases and Cincinnati Children's Hospital for providing the guinea pigs strains used in this study. This work was completed in partial fulfillment of ADP's PhD dissertation.

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