Outer Retinal Corrugations in Rhegmatogenous Retinal Detachment: The Retinal Pigment Epithelium-Photoreceptor Dysregulation Theory.

PURPOSE: Outer retinal folds occur when outer retinal corrugations (ORCs) persist after retinal reattachment with worse functional outcomes. We investigate the pathophysiology of ORCs in vivo. DESIGN: Prospective cohort study. METHODS: Patients with rhegmatogenous retinal detachment (RRD) presenting to St. Michael's Hospital, Toronto, Ontario, Canada, between August 2020 and February 2022 were assessed with swept-source optical coherence tomography (SS-OCT) and ultra-widefield SS-OCT for ORCs. Clinical characteristics of eyes with/without ORCs were compared. Mathematical models were used to deduce mechanical properties leading to ORCs. RESULTS: Sixty-six patients were included. More than half (60.6%, 40/66) were fovea-off and 48.4% (32/66) had ORCs at presentation. All eyes (32/32) with ORCs had retinal pigment epithelium (RPE)-photoreceptor dysregulation for at least 2 days, defined as loss of RPE control with acute, progressive, and extensive RRDs. In all (34/34) eyes without ORCs the RPE was in relative control of the subretinal space with nonprogressive subclinical or small localized or resolving RRDs, or with RPE-photoreceptor dysregulation for fewer than 2 days. Mathematical models indicate that a modulus of elasticity of the outer retina relative to the inner retina of 0.05 to 0.5 leads to ORCs. CONCLUSIONS: ORCs develop with (1) acute exposure of subretinal space to liquified vitreous, (2) for >2 days, that (3) overwhelms RPE capacity, leading to progressive and extensive RRD. Mathematical models suggest that a reduction in the modulus of elasticity of the outer retina occurs such that intrinsic compressive forces, likely related to progressive outer retinal hydration and lateral expansion, lead to ORCs. Understanding the pathophysiology of ORCs has implications for management.

Investigating the correlation of muscle function tests and sarcomere organization in C. elegans.

BACKGROUND: Caenorhabditis elegans has been widely used as a model to study muscle structure and function. Its body wall muscle is functionally and structurally similar to vertebrate skeletal muscle with conserved molecular pathways contributing to sarcomere structure, and muscle function. However, a systematic investigation of the relationship between muscle force and sarcomere organization is lacking. Here, we investigate the contribution of various sarcomere proteins and membrane attachment components to muscle structure and function to introduce C. elegans as a model organism to study the genetic basis of muscle strength. METHODS: We employ two recently developed assays that involve exertion of muscle forces to investigate the correlation of muscle function to sarcomere organization. We utilized a microfluidic pillar-based platform called NemaFlex that quantifies the maximum exertable force and a burrowing assay that challenges the animals to move in three dimensions under a chemical stimulus. We selected 20 mutants with known defects in various substructures of sarcomeres and compared the physiological function of muscle proteins required for force generation and transmission. We also characterized the degree of sarcomere disorganization using immunostaining approaches. RESULTS: We find that mutants with genetic defects in thin filaments, thick filaments, and M-lines are generally weaker, and our assays are successful in detecting the functional changes in response to each sarcomere location tested. We find that the NemaFlex and burrowing assays are functionally distinct informing on different aspects of muscle physiology. Specifically, the burrowing assay has a larger bandwidth in phenotyping muscle mutants, because it could pick ten additional mutants impaired while exerting normal muscle force in NemaFlex. This enabled us to combine their readouts to develop an integrated muscle function score that was found to correlate with the score for muscle structure disorganization. CONCLUSIONS: Our results highlight the suitability of NemaFlex and burrowing assays for evaluating muscle physiology of C. elegans. Using these approaches, we discuss the importance of the studied sarcomere proteins for muscle function and structure. The scoring methodology we have developed enhances the utility of  C. elegans as a genetic model to study muscle function.