{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:51:31Z","timestamp":1791341491272,"version":"4.3.1"},"reference-count":50,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T00:00:00Z","timestamp":1597276800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"SMA Europe"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The purpose of the study was to determine the extent and role of systemic hypoxia in the pathogenesis of spinal muscular atrophy (SMA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Hypoxia was assayed in vivo in early\u2010symptomatic (postnatal day 5) SMA\u2010model mice by pimonidazole and [<jats:sup>18<\/jats:sup>F]\u2010Fluoroazomycin arabinoside injections, which accumulate in hypoxic cells, followed by immunohistochemistry and tracer biodistribution evaluation. Glucose uptake in hypoxic cells was assayed by [<jats:sup>18<\/jats:sup>F]\u2010Fluorodeoxyglucose labeling. In vitro knockdown of Survival Motor Neuron (SMN) was performed on motor neurons and lactate metabolism measured biochemically, whereas cell cycle progression and cell death were assayed by flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All assays found significant levels of hypoxia in multiple organ systems in early symptomatic SMA mouse pups, except aerated tissues such as skin and lungs. This was accompanied by significantly increased glucose uptake in many affected organs, consistent with a metabolic hypoxia response. SMN protein levels were shown to vary widely between motor neuron precursors in vitro, and those with lower levels were most susceptible to cell death. In addition, SMA\u2010model motor neurons were particularly sensitive to hypoxia, with reduced ability to transport lactate out of the cell in hypoxic culture, and a failure in normal cell cycle progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Not only is there widespread tissue hypoxia and multi\u2010organ cellular hypoxic response in SMA model mice, but SMA\u2010model motor neurons are especially susceptible to that hypoxia. The data support the hypothesis that vascular defects leading to hypoxia are a significant contributor to disease progression in SMA, and offer a route for combinatorial, non\u2010SMN related therapy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51134","type":"journal-article","created":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T14:10:37Z","timestamp":1597327837000},"page":"1580-1593","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Widespread tissue hypoxia dysregulates cell and metabolic pathways in SMA"],"prefix":"10.1002","volume":"7","author":[{"given":"Elena","family":"Hernandez\u2010Gerez","sequence":"first","affiliation":[{"name":"Institute of Medical Sciences School of Medicine Medical Sciences and Nutrition University of Aberdeen Foresterhill, Aberdeen AB25 2ZD UK"},{"name":"Euan Macdonald Centre for Motor Neurone Disease Research University of Edinburgh Chancellor's Building Edinburgh EH16 4SB 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