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However, it is not well understood why a large portion of DD patients develop arrhythmia and sudden cardiac death. In the current study, we generated LAMP2 knockout (KO) human iPSC-derived cardiomyocytes (CM), which mimic the LAMP2 dysfunction in DD heart. Morphologic analysis demonstrated the sarcomere disarrangement in LAMP2 KO CMs. In functional studies, LAMP2 KO CMs showed near-normal calcium handling at base level. However, treatment of pro-maturation medium (MM) exaggerated the disease phenotype in the KO cells as they exhibited impaired calcium recycling and increased irregular beating events, which recapitulates the pro-arrhythmia phenotypes of DD patients. Further mechanistic study confirmed that MM treatment significantly enhanced the autophagic stress in the LAMP2 KO CMs, which was accompanied by an increase of both cellular and mitochondrial reactive oxygen species (ROS) levels. Excess ROS accumulation in LAMP2 KO CMs resulted in the over-activation of calcium\/calmodulin dependent protein kinase II\u03b4 (CaMKII\u03b4) and arrhythmogenesis, which was partially rescued by the treatment of ROS scavenger. In summary, our study has revealed ROS induced CaMKII\u03b4 overactivation as a key mechanism that promotes cardiac arrhythmia in DD patients.<\/jats:p>","DOI":"10.3390\/biom13010069","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T03:31:17Z","timestamp":1672371077000},"page":"69","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Metabolic Maturation Exaggerates Abnormal Calcium Handling in a Lamp2 Knockout Human Pluripotent Stem Cell-Derived Cardiomyocyte Model of Danon Disease"],"prefix":"10.3390","volume":"13","author":[{"given":"Robert J.","family":"Barndt","sequence":"first","affiliation":[{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA"},{"name":"Center for Human Genetics, Clemson University, Greenwood, SC 29646, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Tang","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Haugh","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9520-7527","authenticated-orcid":false,"given":"Stephen Y.","family":"Chan","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7900-3073","authenticated-orcid":false,"given":"Haodi","family":"Wu","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA 15213, USA"},{"name":"Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/nan.12587","article-title":"Review: Danon disease: Review of natural history and recent advances","volume":"46","author":"Cenacchi","year":"2020","journal-title":"Neuropathol. 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