{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T21:19:15Z","timestamp":1789161555282,"version":"build-2803163510"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2023,12,19]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Mutations to the co\u2010chaperone protein BAG3 (B\u2010cell lymphoma\u20102\u2013associated athanogene\u20103) are a leading cause of dilated cardiomyopathy (DCM). These mutations often impact the C\u2010terminal BAG domain (residues 420\u2013499), which regulates heat shock protein 70\u2010dependent protein turnover via autophagy. While mutations in other regions are less common, previous studies in patients with DCM found that co\u2010occurrence of 2\n              <jats:italic>BAG3<\/jats:italic>\n              variants (P63A, P380S) led to worse prognosis. However, the underlying mechanism for dysfunction is not fully understood.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              In this study, we used proteomics, Western blots, and myofilament functional assays on left ventricular tissue from patients with nonfailing, DCM, and DCM with\n              <jats:italic>BAG3<\/jats:italic>\n              <jats:sup>63\/380<\/jats:sup>\n              to determine how these mutations impact protein quality control and cardiomyocyte contractile function. We found dysregulated autophagy and increased protein ubiquitination in patients with\n              <jats:italic>BAG3<\/jats:italic>\n              <jats:sup>63\/380<\/jats:sup>\n              compared with nonfailing and DCM, suggesting impaired protein turnover. Expression and myofilament localization of BAG3\u2010binding proteins were also uniquely altered in the\n              <jats:italic>BAG3,<\/jats:italic>\n              <jats:sup>63\/380<\/jats:sup>\n              including abolished localization of the small heat shock protein CRYAB (alpha\u2010crystallin B chain) to the sarcomere. To determine whether these variants impacted sarcomere function, we used cardiomyocyte force\u2010calcium assays and found reduced maximal calcium\u2010activated force in DCM and\n              <jats:italic>BAG3<\/jats:italic>\n              <jats:sup>63\/380<\/jats:sup>\n              . Interestingly, myofilament calcium sensitivity was increased in DCM but not with\n              <jats:italic>BAG3<\/jats:italic>\n              <jats:sup>63\/380<\/jats:sup>\n              , which was not explained by differences in troponin I phosphorylation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Together, our data support that the disease\u2010enhancing mechanism for\n              <jats:italic>BAG3<\/jats:italic>\n              variants outside of the BAG domain is through disrupted protein turnover leading to compromised sarcomere function. These findings suggest a shared mechanism of disease among pathogenic\n              <jats:italic>BAG3<\/jats:italic>\n              variants, regardless of location.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.123.029938","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T10:40:51Z","timestamp":1702896051000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Dysregulated Autophagy and Sarcomere Dysfunction in Patients With Heart Failure With Co\u2010Occurrence of P63A and P380S\n            <i>BAG3<\/i>\n            Variants"],"prefix":"10.1161","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1300-4890","authenticated-orcid":false,"given":"Thomas G.","family":"Martin","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Physiology Loyola University Chicago Stritch School of Medicine Maywood 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AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9057-4021","authenticated-orcid":false,"given":"Charles F.","family":"McTiernan","sequence":"additional","affiliation":[{"name":"The Heart and Vascular Institute, The University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8860-4698","authenticated-orcid":false,"given":"Michael R.","family":"Bristow","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Colorado School of Medicine Denver CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8351-9569","authenticated-orcid":false,"given":"Arthur M.","family":"Feldman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology The Lewis Katz School of Medicine at Temple University Philadelphia 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