Haploinsufficiency of Target of Rapamycin Attenuates Cardiomyopathies in Adult Zebrafish

Author:

Ding Yonghe1,Sun Xiaojing1,Huang Wei1,Hoage Tiffany1,Redfield Margaret1,Kushwaha Sudhir1,Sivasubbu Sridhar1,Lin Xueying1,Ekker Stephen1,Xu Xiaolei1

Affiliation:

1. From the Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN (Y.D., X.S., W.H., T.H., X.L., S.E., X.X.); the Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN (Y.D., X.S., W.H., T.H., M.R., S.K., X.L., X.X.); the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD (W.H.); and the Institute of Genomics and Integrative Biology, Council of Scientific and Industrial...

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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