Basu, B. orcid.org/0000-0002-5434-5202, Karwatka, M. orcid.org/0000-0001-5375-4488, China, B. et al. (5 more authors) (2024) Glycogen myophosphorylase loss causes increased dependence on glucose in iPSC-derived retinal pigment epithelium. Journal of Biological Chemistry, 300 (8). 107569. ISSN 0021-9258
Abstract
Loss of glycogen myophosphorylase (PYGM) expression results in an inability to break down muscle glycogen, leading to McArdle disease—an autosomal recessive metabolic disorder characterized by exercise intolerance and muscle cramps. While previously considered relatively benign, this condition has recently been associated with pattern dystrophy in the retina, accompanied by variable sight impairment, secondary to retinal pigment epithelial (RPE) cell involvement. However, the pathomechanism of this condition remains unclear. In this study, we generated a PYGM-null induced pluripotent stem cell (iPSC) line, and differentiated it into mature RPE to examine structural and functional defects, along with metabolite release into apical and basal media. Mutant RPE exhibited normal photoreceptor outer segment phagocytosis but displayed elevated glycogen levels, reduced transepithelial resistance, and increased cytokine secretion across the epithelial layer compared to isogenic wildtype controls. Additionally, decreased expression of the visual cycle component, RDH11, encoding 11-cis-retinol dehydrogenase, was observed in PYGM-null RPE. While glycolytic flux and oxidative phosphorylation levels in PYGM-null RPE were near normal, the basal oxygen consumption rate (OCR) was increased. OCR in response to physiological levels of lactate was significantly greater in wildtype compared to PYGM-null RPE. Inefficient lactate utilization by mutant RPE resulted in higher glucose dependence and increased glucose uptake from the apical medium in the presence of lactate, suggesting a reduced capacity to spare glucose for photoreceptor use. Metabolic tracing confirmed slower 13C-lactate utilization by PYGM-null RPE. These findings have key implications for retinal health since they likely underlie the vision impairment in individuals with McArdle disease.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Retina; retinal dystrophy; retinal degeneration; retinal metabolism; glucose metabolism; induced pluripotent stem cell (iPS cell) (iPSC) |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Medical Research (LIMR) > Division of Molecular Medicine |
Funding Information: | Funder Grant number MRC (Medical Research Council) MR/T017503/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 16 Jul 2024 13:40 |
Last Modified: | 12 Aug 2024 14:35 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.jbc.2024.107569 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:214828 |