{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:06:45Z","timestamp":1789171605667,"version":"build-2803163510"},"reference-count":59,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T00:00:00Z","timestamp":1649116800000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM124108"],"award-info":[{"award-number":["R01GM124108"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Heart failure (HF) is one of the leading causes of death worldwide and is associated with cardiac metabolic perturbations. Human Type 2 Berardinelli\u2010Seip Congenital Lipodystrophy (BSCL2) disease is caused by mutations in the <jats:italic>BSCL2<\/jats:italic> gene. Global lipodystrophic <jats:italic>Bscl2<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice exhibit hypertrophic cardiomyopathy with reduced cardiac steatosis. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and\/or contractile function remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated mice with cardiomyocyte\u2010specific deletion of <jats:italic>Bscl2<\/jats:italic> (<jats:italic>Bscl2<jats:sup>cKO<\/jats:sup><\/jats:italic>) and studied their cardiac substrate utilisation, bioenergetics, lipidomics and contractile function under baseline or after either a treatment regimen using fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ) or a prevention regimen with high\u2010fat diet (HFD) feeding. Mice with partial ATGL deletion and cardiac\u2010specific deletion of <jats:italic>Bscl2<\/jats:italic> were also generated followed by cardiac phenotyping.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Different from hypertrophic cardiomyopathy in <jats:italic>Bscl2<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice, mice with cardiac\u2010specific deletion of <jats:italic>Bscl2<\/jats:italic> developed systolic dysfunction with dilation. Myocardial BSCL2 deletion led to elevated ATGL expression and FAO along with reduced cardiac lipid contents. Cardiac dysfunction in <jats:italic>Bscl2<jats:sup>cKO<\/jats:sup><\/jats:italic> mice was independent of mitochondrial dysfunction and oxidative stress, but associated with decreased metabolic reserve and ATP levels. Importantly, cardiac dysfunction in <jats:italic>Bscl2<jats:sup>cKO<\/jats:sup><\/jats:italic> mice could be partially reversed by FAO inhibitor TMZ, or prevented by genetic abolishment of one ATGL allele or HFD feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in <jats:italic>Bscl2<jats:sup>cKO<\/jats:sup><\/jats:italic> hearts, which were partially normalised by TMZ or HFD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identified a new form of cardiac dysfunction with excessive lipid utilisation which ultimately causes cardiac substrate depletion and bioenergetics failure. Our findings also uncover a crucial role of BSCL2 in controlling cardiac lipid catabolism and contractile function and provide novel insights into metabolically treating energy\u2010starved HF using FAO inhibitor or HFD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.736","type":"journal-article","created":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T14:24:20Z","timestamp":1649168660000},"source":"Crossref","is-referenced-by-count":12,"title":["BSCL2\/Seipin deficiency in hearts causes cardiac energy deficit and dysfunction via inducing excessive lipid catabolism"],"prefix":"10.1002","volume":"12","author":[{"given":"Hongyi","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Physiology Medical College of Georgia at Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Vascular Biology Center Medical College of Georgia at Augusta University  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