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Lysosomal signaling and function is governed by transcription factor EB (TFEB). In the present study, we hypothesized that DOX caused myocyte injury by impairing lysosomal function and signaling through negative regulation of TFEB. Indeed, we found that DOX repressed cellular TFEB expression, which was associated with impaired cathepsin proteolytic activity across in vivo, ex vivo, and in vitro models of DOX cardiotoxicity. Furthermore, we observed that loss of TFEB was associated with reduction in macroautophagy protein expression, inhibition of autophagic flux, impairments in lysosomal cathepsin B activity, and activation of cell death. Restoration and\/or activation of TFEB in DOX-treated cardiomyocytes prevented DOX-induced suppression of cathepsin B activity, reduced DOX-mediated reactive oxygen species (ROS) overproduction, attenuated activation of caspase-3, and improved cellular viability. Collectively, loss of TFEB inhibits lysosomal autophagy, rendering cardiomyocytes susceptible to DOX-induced proteotoxicity and injury. Our data reveal a novel mechanism wherein DOX primes cardiomyocytes for cell death by depleting cellular TFEB.<\/jats:p>","DOI":"10.1042\/bcj20160385","type":"journal-article","created":{"date-parts":[[2016,8,4]],"date-time":"2016-08-04T01:58:46Z","timestamp":1470275926000},"page":"3769-3789","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":135,"title":["Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy"],"prefix":"10.1042","volume":"473","author":[{"given":"Jordan J.","family":"Bartlett","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada"},{"name":"Dalhousie Medicine New Brunswick, Saint John, NB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Purvi C.","family":"Trivedi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada"},{"name":"Dalhousie Medicine New Brunswick, Saint John, NB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pollen","family":"Yeung","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Department of Medicine (Cardiology), Dalhousie University, Halifax, NS, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra C.","family":"Kienesberger","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada"},{"name":"Dalhousie Medicine New Brunswick, Saint John, NB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Pulinilkunnil","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada"},{"name":"Dalhousie Medicine New Brunswick, Saint John, NB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2016,10,27]]},"reference":[{"key":"2021112216484817800_BCJ-2016-0385C1","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1159\/000265166","article-title":"Doxorubicin cardiomyopathy","volume":"115","author":"Chatterjee","year":"2010","journal-title":"Cardiology"},{"key":"2021112216484817800_BCJ-2016-0385C2","doi-asserted-by":"publisher","first-page":"214","DOI":"10.2174\/157340311799960645","article-title":"Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment","volume":"7","author":"Volkova","year":"2011","journal-title":"Curr. 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