title: Haploinsufficiency of target of rapamycin attenuates cardiomyopathies in adult zebrafish.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Ding
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hoage
authors.forename: Margaret
authors.initials: M
authors.lastname: Redfield
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kushwaha
authors.forename: Sridhar
authors.initials: S
authors.lastname: Sivasubbu
authors.forename: Xueying
authors.initials: X
authors.lastname: Lin
authors.forename: Stephen
authors.initials: S
authors.lastname: Ekker
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Xu
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D009202:Cardiomyopathies / Q000201:enzymology* / Q000235:genetics* / Q000517:prevention & control; D002478:Cells, Cultured; D004195:Disease Models, Animal; D057895:Haploinsufficiency / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*
chemical_list: D029961:Zebrafish Proteins; D058570:TOR Serine-Threonine Kinases