{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:57:11Z","timestamp":1760151431094,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T00:00:00Z","timestamp":1647475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007372","name":"Association Belge Contre les Maladies Neuro-Musculaires","doi-asserted-by":"publisher","award":["2017-2018\/08"],"award-info":[{"award-number":["2017-2018\/08"]}],"id":[{"id":"10.13039\/100007372","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Joint Programme on Rare Diseases (EJP-RD)","award":["EJP RD WP 17"],"award-info":[{"award-number":["EJP RD WP 17"]}]},{"name":"U4 \u2013 OSMYO","award":["U4 \u2013 OSMYO"],"award-info":[{"award-number":["U4 \u2013 OSMYO"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration. Osmotic stress participates to DMD pathology and altered levels of osmolyte pathway members have been reported. The goal of this study was to gain insight in osmoregulatory changes in the mdx mouse model by examining the expression of osmolyte pathway members, including taurine transporter (TauT), sodium myo-inositol co-transporter (SMIT), betaine GABA transporter (BGT), and aldose reductase (AR) in the skeletal muscles and diaphragm of mdx mice aged 4, 8, 12, and 26 weeks. Necrosis was most prominent in 12 week-old mdx mice, whereas the amount of regenerated fibers increased until week 26 in the tibialis anterior. TauT protein levels were downregulated in the tibialis anterior and gastrocnemius of 4 to 12 week-old mdx mice, but not in 26 week-old mice, whereas TauT levels in the diaphragm remained significantly lower in 26 week-old mdx mice. In contrast, SMIT protein levels were significantly higher in the muscles of mdx mice when compared to controls. Our study revealed differential regulation of osmolyte pathway members in mdx muscle, which points to their complex involvement in DMD pathogenesis going beyond general osmotic stress responses. These results highlight the potential of osmolyte pathway members as a research interest and future therapeutic target in dystrophinopathy.<\/jats:p>","DOI":"10.3390\/ijms23063251","type":"journal-article","created":{"date-parts":[[2022,3,20]],"date-time":"2022-03-20T21:30:14Z","timestamp":1647811814000},"page":"3251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Description of Osmolyte Pathways in Maturing Mdx Mice Reveals Altered Levels of Taurine and Sodium\/Myo-Inositol Co-Transporters"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9031-2539","authenticated-orcid":false,"given":"Caroline","family":"Merckx","sequence":"first","affiliation":[{"name":"Department of Neurology, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gwenny","family":"Cosemans","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7062-5319","authenticated-orcid":false,"given":"Jana","family":"Zsch\u00fcntzsch","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center G\u00f6ttingen, 37075 G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8939-0169","authenticated-orcid":false,"given":"Robrecht","family":"Raedt","sequence":"additional","affiliation":[{"name":"4BRAIN, Institute for Neuroscience, Department Head and Skin, Ghent University, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center G\u00f6ttingen, 37075 G\u00f6ttingen, Germany"},{"name":"Department of Neurology and Pain Treatment, Immanuel Klinik R\u00fcdersdorf, University Hospital of the Brandenburg Medical School Theodor Fontane, 15562 R\u00fcdersdorf bei Berlin, Germany"},{"name":"Faculty of Health Sciences Brandenburg, Brandenburg Medical School Theodor Fontane, 15562 R\u00fcdersdorf bei Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9403-4401","authenticated-orcid":false,"given":"Boel","family":"De Paepe","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan L.","family":"De Bleecker","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s13023-020-01430-8","article-title":"Global epidemiology of Duchenne muscular dystrophy: An updated systematic review and meta-analysis","volume":"15","author":"Crisafulli","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41536-018-0045-4","article-title":"Humanizing the mdx mouse model of DMD: The long and the short of it","volume":"3","author":"Yucel","year":"2018","journal-title":"NPJ Regen. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Herbelet, S., Merckx, C., and De Paepe, B. (2021). The PKA-p38MAPK-NFAT5-Organic Osmolytes Pathway in Duchenne Muscular Dystrophy: From Essential Player in Osmotic Homeostasis, Inflammation and Skeletal Muscle Regeneration to Therapeutic Target. Biomedicines, 9.","DOI":"10.3390\/biomedicines9040350"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pediatrneurol.2006.09.016","article-title":"Pathophysiology of Duchenne muscular dystrophy: Current hypotheses","volume":"36","author":"Deconinck","year":"2007","journal-title":"Pediatr. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1007\/s00415-012-6512-8","article-title":"Permanent muscular sodium overload and persistent muscle edema in Duchenne muscular dystrophy: A possible contributor of progressive muscle degeneration","volume":"259","author":"Weber","year":"2012","journal-title":"J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/labinvest.2016.68","article-title":"Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism","volume":"96","author":"Martin","year":"2016","journal-title":"Lab. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2008.03.008","article-title":"Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy","volume":"31","author":"Grounds","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Radley-Crabb, H.G., Marini, J.C., Sosa, H.A., Castillo, L.I., Grounds, M.D., and Fiorotto, M.L. (2014). Dystropathology increases energy expenditure and protein turnover in the mdx mouse model of Duchenne muscular dystrophy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089277"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.nmd.2006.06.011","article-title":"Reduced necrosis of dystrophic muscle by depletion of host neutrophils, or blocking TNF\u03b1 function with Etanercept in mdx mice","volume":"16","author":"Hodgetts","year":"2006","journal-title":"J. Neuromusc. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0022-510X(93)90130-Q","article-title":"Age-related changes in replication of myogenic cells in mdx mice: Quantitative autoradiographic studies","volume":"119","author":"McGeachie","year":"1993","journal-title":"J. Neurol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1046\/j.1469-7580.1999.19420287.x","article-title":"The timing between skeletal muscle myoblast replication and fusion into myotubes, and the stability of regenerated dystrophic myofibres: An autoradiographic study in mdx mice","volume":"194","author":"McGeachie","year":"1999","journal-title":"J. Anat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.biocel.2015.07.016","article-title":"Taurine deficiency, synthesis and transport in the mdx mouse model for Duchenne Muscular Dystrophy","volume":"66","author":"Terrill","year":"2015","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.nmd.2007.11.002","article-title":"Reduced muscle necrosis and long-term benefits in dystrophic mdx mice after cV1q (blockade of TNF) treatment","volume":"18","author":"Radley","year":"2008","journal-title":"Neuromuscul. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.nbd.2006.03.016","article-title":"Cromolyn administration (to block mast cell degranulation) reduces necrosis of dystrophic muscle in mdx mice","volume":"23","author":"Radley","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/0022-510X(94)00276-T","article-title":"Mdx mice show progressive weakness and muscle deterioration with age","volume":"129","author":"Pastoret","year":"1995","journal-title":"J. Neurol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.nmd.2011.07.008","article-title":"A single 30 min treadmill exercise session is suitable for \u2018proof-of concept studies\u2019 in adult mdx mice: A comparison of the early consequences of two different treadmill protocols","volume":"22","author":"Radley","year":"2012","journal-title":"Neuromuscul. Dis."},{"key":"ref_17","unstructured":"Grounds, M. (2014). Quantification of histopathology in haemotoxylin and eosin stained muscle sections. Treat NMD. Neuromuscular Network, Wellstone Muscular Dystrophy Center. DMD_M 1.007."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.nmd.2014.04.006","article-title":"Long-term administration of the TNF blocking drug Remicade (cV1q) to mdx mice reduces skeletal and cardiac muscle fibrosis, but negatively impacts cardiac function","volume":"24","author":"Ermolova","year":"2014","journal-title":"Neuromuscul. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1212\/WNL.0000000000002147","article-title":"Histologic muscular history in steroid-treated and untreated patients with Duchenne dystrophy","volume":"85","author":"Peverelli","year":"2015","journal-title":"Neurology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Herbelet, S., De Paepe, B., and De Bleecker, J.L. (2020). Abnormal NFAT5 physiology in Duchenne muscular dystrophy fibroblasts as a putative explanation for the permanent fibrosis formation in Duchenne muscular dystrophy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217888"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/j.1748-1716.2006.01573.x","article-title":"The taurine transporter: Mechanisms of regulation","volume":"187","author":"Han","year":"2006","journal-title":"Acta Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1113\/jphysiol.2007.146191","article-title":"Up-regulation of hypertonicity-activated myo-inositol transporter SMIT1 by the cell volume-sensitive protein kinase SGK1","volume":"586","author":"Klaus","year":"2008","journal-title":"J. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s00726-006-0291-4","article-title":"The effect of taurine depletion on the contractile properties and fatigue in fast-twitch skeletal muscle of the mouse","volume":"31","author":"Hamilton","year":"2006","journal-title":"Amino Acids"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1096\/fj.03-0496fje","article-title":"Taurine transporter knockout depletes muscle taurine levels and results in severe skeletal muscle impairment but leaves cardiac function uncompromised","volume":"18","author":"Warskulat","year":"2004","journal-title":"FASEB J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7242","DOI":"10.1039\/D0AN00642D","article-title":"Investigation of the effect of taurine supplementation on muscle taurine content in the mdx mouse model of Duchenne muscular dystrophy using chemically specific synchrotron imaging","volume":"145","author":"Terrill","year":"2020","journal-title":"Analyst"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Terrill, J.R., Pinniger, G.J., Nair, K.V., Grounds, M.D., and Arthur, P.G. (2017). Beneficial effects of high dose taurine treatment in juvenile dystrophic mdx mice are offset by growth restriction. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0187317"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.redox.2016.08.016","article-title":"Levels of inflammation and oxidative stress, and a role for taurine in dystropathology of the Golden Retriever Muscular Dystrophy dog model for Duchenne Muscular Dystrophy","volume":"9","author":"Terrill","year":"2016","journal-title":"Redox Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11507","DOI":"10.1096\/fj.201900914RR","article-title":"Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration","volume":"33","author":"Preising","year":"2019","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1152\/japplphysiol.90525.2008","article-title":"Seven days of oral taurine supplementation does not increase muscle taurine content or alter substrate metabolism during prolonged exercise in humans","volume":"105","author":"Galloway","year":"2008","journal-title":"J. Appl. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"C1325","DOI":"10.1152\/ajpcell.1999.276.6.C1325","article-title":"Alternate splicing in human Na+-MI cotransporter gene yields differentially regulated transport isoforms","volume":"276","author":"Porcellati","year":"1999","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1002\/ijc.24249","article-title":"Induction of myeloid-derived suppressor cells by tumor exosomes","volume":"124","author":"Xiang","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"846","DOI":"10.3389\/fneur.2018.00846","article-title":"Induction of osmolyte pathways in skeletal muscle inflammation: Novel biomarkers for myositis","volume":"9","author":"Weis","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0022-510X(96)00135-9","article-title":"An in vivo and in vitro 1H-magnetic resonance spectroscopy study of mdx mouse brain: Abnormal development or neural necrosis?","volume":"141","author":"Tracey","year":"1996","journal-title":"J. Neurol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1002\/pmic.201200578","article-title":"Proteomic profiling of cardiomyopathic tissue from the aged mdx model of Duchenne muscular dystrophy reveals a drastic decrease in laminin, nidogen and annexin","volume":"13","author":"Holland","year":"2013","journal-title":"Proteomics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/6\/3251\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:38:34Z","timestamp":1760135914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/6\/3251"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,17]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23063251"],"URL":"https:\/\/doi.org\/10.3390\/ijms23063251","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,3,17]]}}}