Haploinsufficiency of Target of Rapamycin Attenuates Cardiomyopathies in Adult Zebrafish

• Published in: Circulation research Vol. 109; no. 6; pp. 658 - 669
• Main Authors: Ding, Yonghe, Sun, Xiaojing, Huang, Wei, Hoage, Tiffany, Redfield, Margaret, Kushwaha, Sudhir, Sivasubbu, Sridhar, Lin, Xueying, Ekker, Stephen, Xu, Xiaolei
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 02.09.2011; Lippincott Williams & Wilkins
• Subjects: Aging - genetics; Anemias. Hemoglobinopathies; Animals; Animals, Genetically Modified; Biological and medical sciences; Cardiology. Vascular system; Cardiomyopathies - enzymology; Cardiomyopathies - genetics; Cardiomyopathies - prevention & control; Cells, Cultured; Danio rerio; Disease Models, Animal; Diseases of red blood cells; Freshwater; Fundamental and applied biological sciences. Psychology; Haploinsufficiency - genetics; Heart; Hematologic and hematopoietic diseases; Medical sciences; Myocarditis. Cardiomyopathies; TOR Serine-Threonine Kinases - biosynthesis; TOR Serine-Threonine Kinases - deficiency; TOR Serine-Threonine Kinases - genetics; Vertebrates: cardiovascular system; Zebrafish; Zebrafish Proteins - biosynthesis; Zebrafish Proteins - deficiency; Zebrafish Proteins - genetics; Sirolimus; Cardiomyopathy; Cardiovascular disease; Hemopathy; Myocardial disease; Doxorubicin; Macrocycle; Isomerases; Heart disease; Pisces; Adult; Protein synthesis inhibitor; Human; DNA topoisomerase (ATP-hydrolysing); Enzyme; Anemia; Enzyme inhibitor; Lactone; Topoisomerase II inhibitor; Macrolide; Vertebrata; Brachydanio rerio; cardiotoxicity; Mammalia; Anthracyclins; Circulatory system; target of rapamycin; zebrafish
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.248260

RATIONALE:Although a cardioprotective function of target of rapamycin (TOR) signaling inhibition has been suggested by pharmacological studies using rapamycin, genetic evidences are still lacking. We explored adult zebrafish as a novel vertebrate model for dissecting signaling pathways in cardiomyopathy. OBJECTIVE:We generated the second adult zebrafish cardiomyopathy model induced by doxorubicin. By genetically analyzing both the doxorubicin and our previous established anemia-induced cardiomyopathy models, we decipher the functions of TOR signaling in cardiomyopathies of different etiology. METHODS AND RESULTS:Along the progression of both cardiomyopathy models, we detected dynamic TOR activity at different stages of pathogenesis as well as distinct effects of TOR signaling inhibition. Nevertheless, cardiac enlargement in both models can be effectively attenuated by inhibition of TOR signaling through short-term rapamycin treatment. To assess the long-term effects of TOR reduction, we used a zebrafish target of rapamycin (ztor) mutant identified from an insertional mutagenesis screen. We show that TOR haploinsufficiency in the ztor heterozygous fish improved cardiac function, prevented pathological remodeling events, and ultimately reduced mortality in both adult fish models of cardiomyopathy. Mechanistically, these cardioprotective effects are conveyed by the antihypertrophy, antiapoptosis, and proautophagy function of TOR signaling inhibition. CONCLUSIONS:Our results prove adult zebrafish as a conserved novel vertebrate model for human cardiomyopathies. Moreover, we provide the first genetic evidence to demonstrate a long-term cardioprotective effect of TOR signaling inhibition on at least 2 cardiomyopathies of distinct etiology, despite dynamic TOR activities during their pathogenesis.