{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:51:48Z","timestamp":1753890708484,"version":"3.41.2"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T00:00:00Z","timestamp":1718323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic inflammation during growth, resulting in progressive generalized weakness of the skeletal and cardiac muscles. We previously demonstrated the therapeutic effects of systemic administration of dental pulp mesenchymal stromal cells (DPSCs) in a DMD animal model. We showed preservation of long-term muscle function and slowing of disease progression. However, little is known regarding the effects of cell therapy on the metabolic abnormalities in DMD. Therefore, here, we aimed to investigate the mechanisms underlying the immunosuppressive effects of DPSCs and their influence on DMD metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A comprehensive metabolomics-based approach was employed, and an ingenuity pathway analysis was performed to identify dystrophy-specific metabolomic impairments in the <jats:italic>mdx<\/jats:italic> mice to assess the therapeutic response to our established systemic DPSC-mediated cell therapy approach.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and Discussion<\/jats:title><jats:p>We identified DMD-specific impairments in metabolites and their responses to systemic DPSC treatment. Our results demonstrate the feasibility of the metabolomics-based approach and provide insights into the therapeutic effects of DPSCs in DMD. Our findings could help to identify molecular marker targets for therapeutic intervention and predict long-term therapeutic efficacy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2024.1363541","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T05:14:54Z","timestamp":1718342094000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterization of disease-specific alterations in metabolites and effects of mesenchymal stromal cells on dystrophic muscles"],"prefix":"10.3389","volume":"12","author":[{"given":"Yuko","family":"Nitahara-Kasahara","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillermo","family":"Posadas-Herrera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunio","family":"Hirai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Oda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriko","family":"Snagu-Miyamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Yamanashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Okada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"38","DOI":"10.3390\/metabo7030038","article-title":"Non-targeted metabolomics analysis of golden retriever muscular dystrophy-affected muscles reveals alterations in arginine and proline metabolism, and elevations in glutamic and oleic acid in vivo","volume":"7","author":"Abdullah","year":"2017","journal-title":"Metabolites"},{"key":"B2","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1152\/physrev.00007.2015","article-title":"Absence of dystrophin disrupts skeletal muscle signaling: roles of Ca2+, reactive oxygen species, and nitric oxide in the development of muscular dystrophy","volume":"96","author":"Allen","year":"2016","journal-title":"Physiol. Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e0153461","DOI":"10.1371\/journal.pone.0153461","article-title":"Discovery of metabolic biomarkers for Duchenne muscular dystrophy within a natural history study","volume":"11","author":"Boca","year":"2016","journal-title":"PLoS One"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1073\/pnas.81.4.1189","article-title":"X chromosome-linked muscular dystrophy (mdx) in the mouse","volume":"81","author":"Bulfield","year":"1984","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"609277","DOI":"10.3389\/fimmu.2020.609277","article-title":"Key metabolic pathways in MSC-mediated immunomodulation: implications for the prophylaxis and treatment of graft versus host disease","volume":"11","author":"Burnham","year":"2020","journal-title":"Front. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/0009-8981(95)06164-9","article-title":"Purine and carnitine metabolism in muscle of patients with Duchenne muscular dystrophy","volume":"243","author":"Camina","year":"1995","journal-title":"Clin. Chim. Acta"},{"key":"B7","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/0092-8674(95)90344-5","article-title":"Three muscular dystrophies: loss of cytoskeleton-extracellular matrix linkage","volume":"80","author":"Campbell","year":"1995","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1038\/s41598-021-81090-1","article-title":"Muscle metabolic remodelling patterns in Duchenne muscular dystrophy revealed by ultra-high-resolution mass spectrometry imaging","volume":"11","author":"Dabaj","year":"2021","journal-title":"Sci. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/345315a0","article-title":"Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle","volume":"345","author":"Ervasti","year":"1990","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1097\/00007890-196803000-00009","article-title":"Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues","volume":"6","author":"Friedenstein","year":"1968","journal-title":"Transplantation"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4212","DOI":"10.1093\/hmg\/ddv154","article-title":"Second-generation compound for the modulation of utrophin in the therapy of DMD","volume":"24","author":"Guiraud","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1634\/stemcells.2006-0335","article-title":"Concise review: multipotent mesenchymal stromal cells in blood","volume":"25","author":"He","year":"2007","journal-title":"Stem Cells"},{"key":"B13","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.cellimm.2009.10.006","article-title":"Mesenchymal stem cells as anti-inflammatories: implications for treatment of Duchenne muscular dystrophy","volume":"260","author":"Ichim","year":"2010","journal-title":"Cell Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1089\/ten.2006.0192","article-title":"Isolation and characterization of postnatal stem cells from human dental tissues","volume":"13","author":"Jo","year":"2007","journal-title":"Tissue Eng."},{"key":"B15","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3390\/metabo8040061","article-title":"Metabolomic analyses reveal extensive progenitor cell deficiencies in a mouse model of Duchenne muscular dystrophy","volume":"8","author":"Joseph","year":"2018","journal-title":"Metabolites"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1097\/00001756-199704140-00022","article-title":"Increased cerebral choline-compounds in Duchenne muscular dystrophy","volume":"8","author":"Kato","year":"1997","journal-title":"Neuroreport"},{"key":"B17","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.yjmcc.2007.05.015","article-title":"Metabolic and signaling alterations in dystrophin-deficient hearts precede overt cardiomyopathy","volume":"43","author":"Khairallah","year":"2007","journal-title":"J. Mol. Cell Cardiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"3175","DOI":"10.1073\/pnas.85.9.3175","article-title":"Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain","volume":"85","author":"Kohen","year":"1988","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B19","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s13395-017-0124-z","article-title":"The golden retriever model of Duchenne muscular dystrophy","volume":"7","author":"Kornegay","year":"2017","journal-title":"Skelet. Muscle"},{"key":"B20","doi-asserted-by":"publisher","first-page":"eabh4423","DOI":"10.1126\/sciadv.abh4423","article-title":"Inhibition of sphingolipid de novo synthesis counteracts muscular dystrophy","volume":"8","author":"Laurila","year":"2022","journal-title":"Sci. Adv."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e4075","DOI":"10.1002\/nbm.4075","article-title":"Age-dependent changes in metabolite profile and lipid saturation in dystrophic mice","volume":"32","author":"Lee-McMullen","year":"2019","journal-title":"NMR Biomed."},{"key":"B22","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s13395-023-00325-z","article-title":"Biomarkers for Duchenne muscular dystrophy progression: impact of age in the mdx tongue spared muscle","volume":"13","author":"Lorena","year":"2023","journal-title":"Skelet. Muscle"},{"key":"B23","doi-asserted-by":"publisher","first-page":"193","DOI":"10.3390\/metabo12020193","article-title":"The role of taurine in skeletal muscle functioning and its potential as a supportive treatment for Duchenne muscular dystrophy","volume":"12","author":"Merckx","year":"2022","journal-title":"Metabolites"},{"key":"B24","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s13287-020-02099-3","article-title":"Dental pulp stem cells can improve muscle dysfunction in animal models of Duchenne muscular dystrophy","volume":"12","author":"Nitahara-Kasahara","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"B25","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.cellimm.2008.04.003","article-title":"Immunological properties of umbilical cord blood-derived mesenchymal stromal cells","volume":"251","author":"Oh","year":"2008","journal-title":"Cell Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.cellimm.2016.08.008","article-title":"The paracrine immunomodulatory interactions between the human dental pulp derived mesenchymal stem cells and CD4 T cell subsets","volume":"310","author":"Ozdemir","year":"2016","journal-title":"Cell Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/0010-406X(70)90569-4","article-title":"A comparative study of the effect of carnosine on myofibrillar-ATPase activity of vertebrate and invertebrate muscles","volume":"37","author":"Parker","year":"1970","journal-title":"Comp. Biochem. Physiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"15850","DOI":"10.1074\/jbc.271.27.15850","article-title":"The structural basis of the myosin ATPase activity","volume":"271","author":"Rayment","year":"1996","journal-title":"J. Biol. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"111511","DOI":"10.1016\/j.yexcr.2019.111511","article-title":"MSC-triggered metabolomic alterations in liver-resident immune cells isolated from CCl(4)-induced mouse ALI model","volume":"383","author":"Shi","year":"2019","journal-title":"Exp. Cell Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.1126\/science.2662404","article-title":"The molecular basis of muscular dystrophy in the mdx mouse: a point mutation","volume":"244","author":"Sicinski","year":"1989","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.matbio.2018.01.014","article-title":"Regulation of fibrosis in muscular dystrophy","author":"Smith","year":"2018","journal-title":"Matrix Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2442","DOI":"10.1111\/jcmm.13543","article-title":"Cross-sectional serum metabolomic study of multiple forms of muscular dystrophy","volume":"22","author":"Spitali","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.lfs.2016.01.032","article-title":"Metabolic status of patients with muscular dystrophy in early phase of the disease: in vitro, high resolution NMR spectroscopy based metabolomics analysis of serum","volume":"151","author":"Srivastava","year":"2016","journal-title":"Life Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1002\/cphy.c170052","article-title":"Immunobiology of inherited muscular dystrophies","volume":"8","author":"Tidball","year":"2018","journal-title":"Compr. Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s13023-017-0652-y","article-title":"Therapeutic strategies to address neuronal nitric oxide synthase deficiency and the loss of nitric oxide bioavailability in Duchenne Muscular Dystrophy","volume":"12","author":"Timpani","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1093\/brain\/119.3.1039","article-title":"Brain metabolism is abnormal in the mdx model of Duchenne muscular dystrophy","volume":"119","author":"Tracey","year":"1996","journal-title":"Brain"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1093\/humrep\/deh279","article-title":"Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol","volume":"19","author":"Tsai","year":"2004","journal-title":"Hum. Reprod."},{"key":"B38","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1093\/hmg\/ddz309","article-title":"Longitudinal metabolomic analysis of plasma enables modeling disease progression in Duchenne muscular dystrophy mouse models","volume":"29","author":"Tsonaka","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"B39","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1186\/s13023-023-02885-1","article-title":"The metabolomic plasma profile of patients with Duchenne muscular dystrophy: providing new evidence for its pathogenesis","volume":"18","author":"Xu","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1002\/jcp.21210","article-title":"Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo","volume":"214","author":"Zannettino","year":"2008","journal-title":"J. Cell Physiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1002\/term.71","article-title":"In vivo evaluation of human dental pulp stem cells differentiated towards multiple lineages","volume":"2","author":"Zhang","year":"2008","journal-title":"J. Tissue Eng. Regen. Med."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2024.1363541\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T05:14:56Z","timestamp":1718342096000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2024.1363541\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,14]]},"references-count":41,"alternative-id":["10.3389\/fcell.2024.1363541"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2024.1363541","relation":{},"ISSN":["2296-634X"],"issn-type":[{"type":"electronic","value":"2296-634X"}],"subject":[],"published":{"date-parts":[[2024,6,14]]},"article-number":"1363541"}}