{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:38:08Z","timestamp":1790836688209,"version":"4.1.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T00:00:00Z","timestamp":1667779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Cardiomyocytes differentiated from human induced Pluripotent Stem Cells (hiPSC- CMs) are a unique source for modelling inherited cardiomyopathies. In particular, the possibility of observing maturation processes in a simple culture dish opens novel perspectives in the study of early-disease defects caused by genetic mutations before the onset of clinical manifestations. For instance, calcium handling abnormalities are considered as a leading cause of cardiomyocyte dysfunction in several genetic-based dilated cardiomyopathies, including rare types such as Duchenne Muscular Dystrophy (DMD)-associated cardiomyopathy. To better define the maturation of calcium handling we simultaneously measured action potential and calcium transients (Ca-Ts) using fluorescent indicators at specific time points. We combined micropatterned substrates with long-term cultures to improve maturation of hiPSC-CMs (60, 75 or 90 days post-differentiation). Control-(hiPSC)-CMs displayed increased maturation over time (90 vs 60 days), with longer action potential duration (APD), increased Ca-T amplitude, faster Ca-T rise (time to peak) and Ca-T decay (RT50). The progressively increased contribution of the SR to Ca release (estimated by post-rest potentiation or Caffeine-induced Ca-Ts) appeared as the main determinant of the progressive rise of Ca-T amplitude during maturation. As an example of severe cardiomyopathy with early onset, we compared hiPSC-CMs generated from a DMD patient (DMD-\u0394Exon50) and a CRISPR-Cas9 genome edited cell line isogenic to the healthy control with deletion of a G base at position 263 of the DMD gene (c.263delG-CMs). In DMD-hiPSC-CMs, changes of Ca-Ts during maturation were less pronounced: indeed, DMD cells at 90 days showed reduced Ca-T amplitude and faster Ca-T rise and RT50, as compared with control hiPSC-CMs. Caffeine-Ca-T was reduced in amplitude and had a slower time course, suggesting lower SR calcium content and NCX function in DMD vs control cells. Nonetheless, the inotropic and lusitropic responses to forskolin were preserved. CRISPR-induced c.263delG-CM line recapitulated the same developmental calcium handling alterations observed in DMD-CMs. We then tested the effects of micropatterned substrates with higher stiffness. In control hiPSC-CMs, higher stiffness leads to higher amplitude of Ca-T with faster decay kinetics. In hiPSC-CMs lacking full-length dystrophin, however, stiffer substrates did not modify Ca-Ts but only led to higher SR Ca content. These findings highlighted the inability of dystrophin-deficient cardiomyocytes to adjust their calcium homeostasis in response to increases of extracellular matrix stiffness, which suggests a mechanism occurring during the physiological and pathological development (i.e. fibrosis).<\/jats:p>","DOI":"10.3389\/fphys.2022.1030920","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T05:11:05Z","timestamp":1667797865000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Calcium handling maturation and adaptation to increased substrate stiffness in human iPSC-derived cardiomyocytes: The impact of full-length dystrophin deficiency"],"prefix":"10.3389","volume":"13","author":[{"given":"Jos\u00e8 Manuel","family":"Pioner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Santini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Palandri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Langione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Grandinetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Querceto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Martella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Mazzantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Scellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucrezia","family":"Giammarino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Lupi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Mazzarotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoife","family":"Gowran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Rovina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosaria","family":"Santoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Pompilio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Tesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Parmeggiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Regnier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Cerbai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Mack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrado","family":"Poggesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Ferrantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Coppini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.hrthm.2012.12.016","article-title":"Inhibition of CaMKII phosphorylation of RyR2 prevents inducible ventricular arrhythmias in mice with Duchenne muscular dystrophy","volume":"10","author":"Ather","year":"2013","journal-title":"Heart Rhythm."},{"key":"B2","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nm.1916","article-title":"Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle","volume":"15","author":"Bellinger","year":"2009","journal-title":"Nat. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.yjmcc.2020.06.003","article-title":"Isogenic models of hypertrophic cardiomyopathy unveil differential phenotypes and mechanism-driven therapeutics","volume":"145","author":"Bhagwan","year":"2020","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"20417314221119628","DOI":"10.1177\/20417314221119628","article-title":"Full-length dystrophin deficiency leads to contractile and calcium transient defects in human engineered heart tissues","volume":"13","author":"Bremner","year":"2022","journal-title":"J. Tissue Eng."},{"key":"B5","doi-asserted-by":"publisher","first-page":"21923","DOI":"10.1021\/acsami.5b11671","article-title":"Nanotopography-induced structural anisotropy and sarcomere development in human cardiomyocytes derived from induced pluripotent stem cells","volume":"8","author":"Carson","year":"2016","journal-title":"ACS Appl. Mat. Interfaces"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2169","DOI":"10.1016\/j.stemcr.2021.04.018","article-title":"Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes","volume":"16","author":"Chang","year":"2021","journal-title":"Stem Cell Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.stemcr.2021.12.019","article-title":"Human iPSC model reveals a central role for NOX4 and oxidative stress in Duchenne cardiomyopathy","volume":"17","author":"Duelen","year":"2022","journal-title":"Stem Cell Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1111\/jcmm.14124","article-title":"Electrophysiological abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from Duchenne muscular dystrophy patients","volume":"23","author":"Eisen","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.cell.2006.06.044","article-title":"Matrix elasticity directs stem cell lineage specification","volume":"126","author":"Engler","year":"2006","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"13591","DOI":"10.1074\/jbc.R200021200","article-title":"Costameres: the achilles' heel of herculean muscle","volume":"278","author":"Ervasti","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1016\/j.matbio.2018.02.016","article-title":"Non-glycanated biglycan and LTBP4: Leveraging the extracellular matrix for Duchenne muscular dystrophy therapeutics","author":"Fallon","year":"2018","journal-title":"Matrix Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.ceca.2009.06.002","article-title":"Pathways of abnormal stress-induced Ca2+ influx into dystrophic mdx cardiomyocytes","volume":"46","author":"Fanchaouy","year":"2009","journal-title":"Cell calcium"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1073\/pnas.0908540107","article-title":"Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy","volume":"107","author":"Fauconnier","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B14","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3233\/JND-160194","article-title":"Cardiac involvement classification and therapeutic management in patients with Duchenne muscular dystrophy","volume":"4","author":"Fayssoil","year":"2017","journal-title":"J. Neuromuscul. Dis."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e005407","DOI":"10.1161\/JAHA.116.005407","article-title":"Pathogenesis of hypertrophic cardiomyopathy is mutation rather than disease specific: A comparison of the cardiac troponin T E163R and R92Q mouse models","volume":"6","author":"Ferrantini","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"B16","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/s0046-8177(76)80053-6","article-title":"The pathology of the heart in progressive muscular dystrophy: epimyocardial fibrosis","volume":"7","author":"Frankel","year":"1976","journal-title":"Hum. Pathol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1007\/s00424-021-02571-w","article-title":"A detailed characterization of the hyperpolarization-activated \"funny\" current (If) in human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes with pacemaker activity","volume":"473","author":"Giannetti","year":"2021","journal-title":"Pflugers Arch."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.hfc.2021.07.013","article-title":"The influence of genotype on the phenotype, clinical course, and risk of adverse events in children with hypertrophic cardiomyopathy","volume":"18","author":"Girolami","year":"2022","journal-title":"Heart Fail. Clin."},{"key":"B19","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/j.scr.2013.12.004","article-title":"Dystrophin-deficient cardiomyocytes derived from human urine: new biologic reagents for drug discovery","volume":"12","author":"Guan","year":"2014","journal-title":"Stem Cell Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"E53","DOI":"10.3390\/cells8010053","article-title":"Dystrophin deficiency leads to genomic instability in human pluripotent stem cells via NO synthase-induced oxidative stress","volume":"8","author":"Jelinkova","year":"2019","journal-title":"Cells"},{"key":"B21","doi-asserted-by":"publisher","first-page":"535","DOI":"10.3389\/fbioe.2020.00535","article-title":"DMD pluripotent stem cell derived cardiac cells recapitulate in vitro human cardiac pathophysiology","volume":"8","author":"Jelinkova","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1096\/fj.15-280982","article-title":"Time-dependent evolution of functional vs. remodeling signaling in induced pluripotent stem cell-derived cardiomyocytes and induced maturation with biomechanical stimulation","volume":"30","author":"Jung","year":"2016","journal-title":"Fed. Am. Soc. Exp. Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1161\/CIRCULATIONAHA.121.056198","article-title":"Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome","volume":"144","author":"Krane","year":"2021","journal-title":"Circulation"},{"key":"B24","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1093\/cvr\/cvs425","article-title":"Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy","volume":"97","author":"Kyrychenko","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"95918","DOI":"10.1172\/jci.insight.95918","article-title":"Functional correction of dystrophin actin binding domain mutations by genome editing","volume":"2","author":"Kyrychenko","year":"2017","journal-title":"JCI insight"},{"key":"B26","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.ijcard.2022.03.050","article-title":"Diagnosis and management of rare cardiomyopathies in adult and paediatric patients. A position paper of the Italian society of cardiology (SIC) and Italian society of paediatric cardiology (SICP)","volume":"357","author":"Limongelli","year":"2022","journal-title":"Int. J. Cardiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1089\/scd.2012.0490","article-title":"Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells","volume":"22","author":"Lundy","year":"2013","journal-title":"Stem Cells Dev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1007\/s12195-015-0413-8","article-title":"Nanopatterned human iPSC-based model of a dystrophin-null cardiomyopathic phenotype","volume":"8","author":"Macadangdang","year":"2015","journal-title":"Cell. Mol. Bioeng."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1101\/456301","article-title":"Engineered developmental niche enables predictive phenotypic screening in human dystrophic cardiomyopathy","author":"Macadangdang","year":"2018"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1007\/s00246-019-02165-5","article-title":"Learn from your elders: developmental biology lessons to guide maturation of stem cell-derived cardiomyocytes","volume":"40","author":"Marchiano","year":"2019","journal-title":"Pediatr. Cardiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"12985","DOI":"10.3390\/ijms222312985","article-title":"Skeletal ryanodine receptors are involved in impaired myogenic differentiation in Duchenne muscular dystrophy patients","volume":"22","author":"Meyer","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.yjmcc.2016.09.004","article-title":"Deficient cMyBP-C protein expression during cardiomyocyte differentiation underlies human hypertrophic cardiomyopathy cellular phenotypes in disease specific human ES cell derived cardiomyocytes","volume":"99","author":"Monteiro da Rocha","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/s41591-019-0738-2","article-title":"Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy","volume":"26","author":"Moretti","year":"2020","journal-title":"Nat. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1002\/adhm.201300620","article-title":"Role of extracellular matrix signaling cues in modulating cell fate commitment for cardiovascular tissue engineering","volume":"3","author":"Nakayama","year":"2014","journal-title":"Adv. Healthc. Mat."},{"key":"B35","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1007\/s12265-009-9137-2","article-title":"The many faces of hypertrophic cardiomyopathy: from developmental biology to clinical practice","volume":"2","author":"Olivotto","year":"2009","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1038\/nrcardio.2009.9","article-title":"Developmental origins of hypertrophic cardiomyopathy phenotypes: a unifying hypothesis","volume":"6","author":"Olivotto","year":"2009","journal-title":"Nat. Rev. Cardiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"E3799","DOI":"10.3390\/ijms20153799","article-title":"Optical investigation of action potential and calcium handling maturation of hiPSC-cardiomyocytes on biomimetic substrates","volume":"20","author":"Pioner","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1093\/cvr\/cvz109","article-title":"Absence of full-length dystrophin impairs normal maturation and contraction of cardiomyocytes derived from human induced pluripotent stem cells","volume":"116","author":"Pioner","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"368","DOI":"10.3389\/fphys.2020.00368","article-title":"Advances in stem cell modeling of dystrophin-associated disease: Implications for the wider world of dilated cardiomyopathy","volume":"11","author":"Pioner","year":"2020","journal-title":"Front. Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.yjmcc.2022.02.001","article-title":"The harder the climb the better the view: The impact of substrate stiffness on cardiomyocyte fate","volume":"166","author":"Querceto","year":"2022","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1083\/jcb.201212142","article-title":"The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy","volume":"201","author":"Rahimov","year":"2013","journal-title":"J. Cell Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"12705","DOI":"10.1073\/pnas.1508073112","article-title":"Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness","volume":"112","author":"Ribeiro","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B43","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.yjmcc.2020.03.008","article-title":"A cardiomyocyte show of force: A fluorescent alpha-actinin reporter line sheds light on human cardiomyocyte contractility versus substrate stiffness","volume":"141","author":"Ribeiro","year":"2020","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2455","DOI":"10.1016\/j.bpj.2011.09.057","article-title":"Substrate stiffness increases twitch power of neonatal cardiomyocytes in correlation with changes in myofibril structure and intracellular calcium","volume":"101","author":"Rodriguez","year":"2011","journal-title":"Biophys. J."},{"key":"B45","doi-asserted-by":"publisher","first-page":"8203950","DOI":"10.1155\/2019\/8203950","article-title":"Unchain my heart: Integrins at the basis of iPSC cardiomyocyte differentiation","volume":"2019","author":"Santoro","year":"2019","journal-title":"Stem Cells Int."},{"key":"B46","doi-asserted-by":"publisher","first-page":"H1992","DOI":"10.1152\/ajpheart.00602.2009","article-title":"Hypersensitivity of excitation-contraction coupling in dystrophic cardiomyocytes","volume":"297","author":"Ullrich","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.yjmcc.2015.11.009","article-title":"Crosstalk between RyR2 oxidation and phosphorylation contributes to cardiac dysfunction in mice with Duchenne muscular dystrophy","volume":"89","author":"Wang","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"4974","DOI":"10.1038\/ncomms5974","article-title":"In vivo single-molecule imaging identifies altered dynamics of calcium channels in dystrophin-mutant C. elegans","volume":"5","author":"Zhan","year":"2014","journal-title":"Nat. Commun."},{"key":"B49","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.omtn.2022.07.024","article-title":"A humanized knockin mouse model of Duchenne muscular dystrophy and its correction by CRISPR-Cas9 therapeutic gene editing","volume":"29","author":"Zhang","year":"2022","journal-title":"Mol. Ther. Nucleic Acids"}],"updated-by":[{"DOI":"10.3389\/fphys.2023.1222400","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000}}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.1030920\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T14:41:16Z","timestamp":1686580876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.1030920\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,7]]},"references-count":49,"alternative-id":["10.3389\/fphys.2022.1030920"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2022.1030920","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fphys.2023.1222400","asserted-by":"object"}]},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,7]]},"article-number":"1030920"}}