title: Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart.
abstract: BACKGROUND
  Changes in energy substrate metabolism are first responders to hemodynamic stress in the heart. We have previously shown that hexose-6-phosphate levels regulate mammalian target of rapamycin (mTOR) activation in response to insulin. We now tested the hypothesis that inotropic stimulation and increased afterload also regulate mTOR activation via glucose 6-phosphate (G6P) accumulation.
  
  
  RESULTS
  We subjected the working rat heart ex vivo to a high workload in the presence of different energy-providing substrates including glucose, glucose analogues, and noncarbohydrate substrates. We observed an association between G6P accumulation, mTOR activation, endoplasmic reticulum (ER) stress, and impaired contractile function, all of which were prevented by pretreating animals with rapamycin (mTOR inhibition) or metformin (AMPK activation). The histone deacetylase inhibitor 4-phenylbutyrate, which relieves ER stress, also improved contractile function. In contrast, adding the glucose analogue 2-deoxy-d-glucose, which is phosphorylated but not further metabolized, to the perfusate resulted in mTOR activation and contractile dysfunction. Next we tested our hypothesis in vivo by transverse aortic constriction in mice. Using a micro-PET system, we observed enhanced glucose tracer analog uptake and contractile dysfunction preceding dilatation of the left ventricle. In contrast, in hearts overexpressing SERCA2a, ER stress was reduced and contractile function was preserved with hypertrophy. Finally, we examined failing human hearts and found that mechanical unloading decreased G6P levels and ER stress markers.
  
  
  CONCLUSIONS
  We propose that glucose metabolic changes precede and regulate functional (and possibly also structural) remodeling of the heart. We implicate a critical role for G6P in load-induced mTOR activation and ER stress.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Shiraj
authors.initials: S
authors.lastname: Sen
authors.forename: Bijoy K
authors.initials: BK
authors.lastname: Kundu
authors.forename: Henry Cheng-Ju
authors.initials: HC
authors.lastname: Wu
authors.forename: S Shahrukh
authors.initials: SS
authors.lastname: Hashmi
authors.forename: Patrick
authors.initials: P
authors.lastname: Guthrie
authors.forename: Landon W
authors.initials: LW
authors.lastname: Locke
authors.forename: R Jack
authors.initials: RJ
authors.lastname: Roy
authors.forename: G Paul
authors.initials: GP
authors.lastname: Matherne
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Berr
authors.forename: Matthew
authors.initials: M
authors.lastname: Terwelp
authors.forename: Brian
authors.initials: B
authors.lastname: Scott
authors.forename: Sylvia
authors.initials: S
authors.lastname: Carranza
authors.forename: O Howard
authors.initials: OH
authors.lastname: Frazier
authors.forename: David K
authors.initials: DK
authors.lastname: Glover
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Dillmann
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
mesh_terms: D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005947:Glucose / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: ER stress; glucose; hypertrophy; mTOR; metabolism