{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:47:14Z","timestamp":1791528434970,"version":"4.3.4"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Cardiac hypertrophy is a major contributor to heart failure development, making its prevention and treatment critical for reducing heart failure\u2013associated mortality. Although alternative splicing is recognized as a key regulatory mechanism in myocardial hypertrophy, the precise pathways involved remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>To investigate the role of MBNL2 (muscleblind-like protein 2) in the heart, we overexpressed MBNL2 in cardiomyocytes via adeno-associated virus serotype 9 delivery. In addition, cardiomyocyte-specific MBNL2 knockout mice were generated, and transverse aortic constriction surgery or isoproterenol injection was performed to induce cardiac hypertrophy and dysfunction in mice. The underlying mechanisms were further investigated using RNA sequencing, alternative splicing analysis, and RNA immunoprecipitation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>MBNL2 expression was significantly increased in the heart tissues from patients with ischemic cardiomyopathy and in mice with cardiac hypertrophy. Cardiac-specific overexpression of MBNL2 induced cardiac hypertrophy and dysfunction. Mechanistically, MBNL2 promoted exon 9 skipping of TPM3 (tropomyosin 3), generating the TPM3 isoform lacking exon 9 (TPM3-\u0394e9). In neonatal mouse cardiomyocytes, TPM3-\u0394e9 knockdown partially reduced oxidative stress and mitigated mitochondrial damage induced by MBNL2 overexpression. Adeno-associated virus serotype 9\u2013mediated knockdown of TPM3-\u0394e9 partially attenuated cardiac hypertrophy in MBNL2-overexpressing mice. Notably, cardiac-specific MBNL2 knockout or TPM3-\u0394e9 knockdown in mice attenuated cardiac dysfunction induced by transverse aortic constriction. Further, we found that elevated TPM3-\u0394e9 was associated with RNF20 (ring finger protein 20) and was accompanied by reduced RNF20 interaction with NCoR1 (nuclear receptor corepressor 1), increased NCoR1 expression, and decreased PPAR\u03b1 (peroxisome proliferator\u2013activated receptor alpha) signaling. The protective effects of MBNL2 or TPM3-\u0394e9 knockdown in hypertrophic cardiomyocytes were partially reversed by treatment with the PPAR\u03b1 inhibitor GW6471.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>This study uncovers a novel, critical role for MBNL2 in pathological cardiac hypertrophy through regulation of TPM3 alternative splicing and mitochondrial function, highlighting MBNL2 as a potential therapeutic target for cardiac hypertrophy and dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.328002","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T09:00:23Z","timestamp":1788339623000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["RNA-Binding Protein MBNL2 Drives Cardiac Hypertrophy and Dysfunction by Facilitating TPM3 Splicing"],"prefix":"10.1161","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8894-4652","authenticated-orcid":true,"given":"Yuanqi","family":"Shi","sequence":"first","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province (Y.S., S.S., H.Z., J.Y., Z.D.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (S.S., P.L., J.L., P.D., J.Z.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."},{"name":"Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province (Y.S., S.S., H.Z., J.Y., Z.D.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0201-9154","authenticated-orcid":true,"given":"Bin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China (B.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengcheng","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (S.S., P.L., J.L., P.D., J.Z.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (S.S., P.L., J.L., P.D., J.Z.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengwei","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (S.S., P.L., J.L., P.D., J.Z.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (S.S., P.L., J.L., P.D., J.Z.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiuling","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology (J.C., Y.L.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1066-1940","authenticated-orcid":true,"given":"Haiyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province (Y.S., S.S., H.Z., J.Y., Z.D.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Lv","sequence":"additional","affiliation":[{"name":"Experimental Animal Center (L.L.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0165-0680","authenticated-orcid":true,"given":"Jiale","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province (Y.S., S.S., H.Z., J.Y., Z.D.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dankun","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of General Surgery (D.L.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2353-4078","authenticated-orcid":true,"given":"Yue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology (J.C., Y.L.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."},{"name":"NHC Key Laboratory of Cell Transplantation (Z.D., Y.L.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5255-3270","authenticated-orcid":true,"given":"Zengxiang","family":"Dong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province (Y.S., S.S., H.Z., J.Y., Z.D.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."},{"name":"NHC Key Laboratory of Cell Transplantation (Z.D., Y.L.), the First Affiliated Hospital, Harbin Medical University, Harbin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.304937"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-018-0007-y"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.2478\/jtim-2022-0025"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/16.suppl_n.19"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.12.031"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax2537"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08909"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00556-8"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-022-00828-0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0380-8"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.11.032"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI120279"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2021.01.006"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.320080"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39965-6"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202308769"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.06.041"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-0436.2006.00060.x"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.184390.114"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.039596"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/cm.21629"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-020-01686-x"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.49906"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.21037\/atm-21-4043"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-023-00327-x"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.043053"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00111.2018"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-023-00887-x"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000141774.29937.e3"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.08.023"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202306986"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0508"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2023.101784"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060614-034316"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.11.036"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10184101"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaf370"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky565"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2024.167456"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.110163"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI186416"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac108"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.125.24641"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23042094"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells8020108"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.008"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2022.06.007"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.02.040"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-020-00707-1"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2439"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.223818"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI10268"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2022.175155"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.12001"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2019.07.006"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.125.327680"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.125.328184"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.125.328002","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T18:00:28Z","timestamp":1791482428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.125.328002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":57,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,10,9]]}},"alternative-id":["10.1161\/CIRCRESAHA.125.328002"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.125.328002","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"assertion":[{"value":"2025-12-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-15","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}