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Because augmentation of <jats:italic>\u03b1B\u2010crystallin<\/jats:italic> and <jats:italic>hspB2<\/jats:italic> was presented in the cortical tubers and lymphangioleiomyomatosis of tuberous sclerosis complex patients, we deciphered the role of <jats:italic>\u03b1B\u2010crystallin<\/jats:italic> and its adjacent duplicate gene, <jats:italic>hspB2<\/jats:italic>, in hyperactive mTOR\u2010induced cardiomyopathy. Cardiac <jats:italic>Tsc1<\/jats:italic> deletion (<jats:italic>T1<\/jats:italic>\u2010hKO) caused mouse mTOR activation and cardiomyopathy. Overexpression of \u03b1B\u2010crystallin and hspB2 was presented in the hearts of these mice. Knockout of <jats:italic>\u03b1B\u2010crystallin\/hspB2<\/jats:italic> reversed deficient <jats:italic>Tsc1<\/jats:italic>\u2010mediated fetal gene expression, mTOR activation, mitochondrial damage, cardiomyocyte vacuolar degeneration, cardiomyocyte size, and fibrosis of <jats:italic>T1<\/jats:italic>\u2010hKO mice. These cardiac\u2010<jats:italic>Tsc1<\/jats:italic>; <jats:italic>\u03b1B\u2010crystallin<\/jats:italic>; <jats:italic>hspB2<\/jats:italic> triple knockout (tKO) mice had improved cardiac function, smaller heart weight to body weight ratio, and reduced lethality compared with <jats:italic>T1<\/jats:italic>\u2010hKO mice. Even though activated mTOR suppressed autophagy in <jats:italic>T1<\/jats:italic>\u2010hKO mice, ablation of <jats:italic>\u03b1B\u2010crystallin<\/jats:italic> and <jats:italic>hspB2<\/jats:italic> failed to restore autophagy in tKO mice. mTOR inhibitors suppressed \u03b1B\u2010crystallin expression in <jats:italic>T1<\/jats:italic>\u2010hKO mice and rat cardiomyocyte line H9C2. Starvation of H9C2 cells activated autophagy and suppressed \u03b1B\u2010crystallin expression. Since inhibition of autophagy restored \u03b1B\u2010crystallin expression in starved H9C2 cells, autophagy is a negative regulator of \u03b1B\u2010crystallin expression. mTOR thus stimulates \u03b1B\u2010crystallin expression through suppression of autophagy. In conclusion, \u03b1B\u2010crystallin and hspB2 play a pivotal role in <jats:italic>Tsc1<\/jats:italic> knockout\u2010related cardiomyopathy and are therapeutic targets of hyperactive mTOR\u2010associated cardiomyopathy.<\/jats:p>","DOI":"10.1002\/jcp.30465","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T09:21:06Z","timestamp":1623230466000},"page":"8110-8121","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["\u03b1B\u2010crystallin\/HSPB2 is critical for hyperactive mTOR\u2010induced cardiomyopathy"],"prefix":"10.1002","volume":"236","author":[{"given":"Lianmei","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College Chinese Academy of Medical Sciences Beijing China"},{"name":"Safety 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