{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:04:44Z","timestamp":1788930284748,"version":"build-2803163510"},"reference-count":76,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2020,1,10]],"date-time":"2020-01-10T00:00:00Z","timestamp":1578614400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["305121"],"award-info":[{"award-number":["305121"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["305444"],"award-info":[{"award-number":["305444"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007423","name":"Duchenne Parent Project","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007423","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Duchenne muscular dystrophy is a severe pediatric neuromuscular disorder caused by the lack of dystrophin. Identification of biomarkers is needed to support and accelerate drug development. Alterations of metabolites levels in muscle and plasma have been reported in pre-clinical and clinical cross-sectional comparisons. We present here a 7-month longitudinal study comparing plasma metabolomic data in wild-type and mdx mice. A mass spectrometry approach was used to study metabolites in up to five time points per mouse at 6, 12, 18, 24 and 30\u00a0weeks of age, providing an unprecedented in depth view of disease trajectories. A total of 106 metabolites were studied. We report a signature of 31 metabolites able to discriminate between healthy and disease at various stages of the disease, covering the acute phase of muscle degeneration and regeneration up to the deteriorating phase. We show how metabolites related to energy production and chachexia (e.g. glutamine) are affected in mdx mice plasma over time. We further show how the signature is connected to molecular targets of nutraceuticals and pharmaceutical compounds currently in development as well as to the nitric oxide synthase pathway (e.g. arginine and citrulline). Finally, we evaluate the signature in a second longitudinal study in three independent mouse models carrying 0, 1 or 2 functional copies of the dystrophin paralog utrophin. In conclusion, we report an in-depth metabolomic signature covering previously identified associations and new associations, which enables drug developers to peripherally assess the effect of drugs on the metabolic status of dystrophic mice.<\/jats:p>","DOI":"10.1093\/hmg\/ddz309","type":"journal-article","created":{"date-parts":[[2019,12,18]],"date-time":"2019-12-18T12:10:18Z","timestamp":1576671018000},"page":"745-755","source":"Crossref","is-referenced-by-count":29,"title":["Longitudinal metabolomic analysis of plasma enables modeling disease progression in Duchenne muscular dystrophy mouse models"],"prefix":"10.1093","volume":"29","author":[{"given":"Roula","family":"Tsonaka","sequence":"first","affiliation":[{"name":"Biomedical Data Sciences, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Signorelli","sequence":"first","affiliation":[{"name":"Biomedical Data Sciences, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"},{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekrem","family":"Sabir","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Seyer","sequence":"first","affiliation":[{"name":"Profilomic SA, Boulogne-Billancourt 92100, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Hettne","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke","family":"Aartsma-Rus","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Spitali","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,1,10]]},"reference":[{"key":"2020033009050340400_ref1","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/S0140-6736(12)61897-2","article-title":"Muscular dystrophies","volume":"381","author":"Mercuri","year":"2013","journal-title":"Lancet (London, England)"},{"key":"2020033009050340400_ref2","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1038\/sj.ejhg.5201478","article-title":"Mutation spectrum leading to an attenuated phenotype in dystrophinopathies","volume":"13","author":"Tuffery-Giraud","year":"2005","journal-title":"Eur. 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Neurol."},{"key":"2020033009050340400_ref6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.nmd.2017.10.004","article-title":"A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy","volume":"28","author":"Goemans","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"2020033009050340400_ref7","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1002\/jcsm.12304","article-title":"Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies","volume":"9","author":"Spitali","year":"2018","journal-title":"J. Cachexia. Sarcopenia Muscle"},{"key":"2020033009050340400_ref8","first-page":"10","article-title":"Comparative mass spectrometric and immunoassay-based proteome analysis in serum of Duchenne muscular dystrophy patients","author":"Oonk","year":"2015","journal-title":"Proteomics. 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