Circulation: Heart Failure HHF Metabolic Efficiency Promotes Protection From Pressure Overload in Hearts Expressing Slow Skeletal Troponin I Carley et al: ssTnI Attenutates Hypertrophic Remodeling CIRCHF/2014/001496 CIRCHF/2014/001496 10.1161/CIRCHEARTFAILURE.114.001496 8 01/20/15 1 Picillo Emily 617-542-5100 617-542-6539 Kirshenbaum, Lorrie University of Manitoba, Winnipeg, Canada Dr. E. Douglas Lewandowski dougl@uic.edu Dr. University of Illinois at Chicago College of Medicine 909 South Wolcott, MC - 801 Chicago Illinois 60612 UNITED STATES 312-413-7261 312-996-2870 20129 Andrew N. Carley University of Illinois at Chicago College of Medicine ancarley@uic.edu 168586 Domenico M. Taglieri University of Illinois at Chicago domenico.taglieri@gmail.com 99803 Jian Bi University of Illinois at Chicago College of Medicine jianbi@uic.edu 217788 R. John Solaro University of Illinois solarorj@uic.edu 23429 E. Douglas Lewandowski University of Illinois at Chicago College of Medicine dougl@uic.edu 20129 05/30/2014 05/30/2014 11/20/2014 11/25/2014 11/25/2014 01/20/2015 Original Articles <p><b><i>Background</i></b>—The failing heart displays increased glycolytic flux that is not matched by a commensurate increase in glucose oxidation. This mismatch induces increased anaplerotic flux and inefficient glucose metabolism. We previously found adult transgenic mouse hearts expressing the fetal troponin I isoform, (ssTnI) to be protected from ischemia by increased glycolysis. In the present study we investigated the metabolic response of adult mouse hearts expressing ssTnI to chronic pressure overload. </p><p><b><i>Methods and Results</i></b>—At 2-3 months of age ssTnI mice or their nontransgenic (NTG) littermates underwent aortic constriction (TAC). TAC induced a 25% increase in NTG heart size but only a 7% increase in ssTnI hearts (P<0.05). NTG TAC developed diastolic dysfunction (65% increased E/A ratio), while the E/A ratio actually decreased in ssTnI TAC. Isolated perfused hearts from NTG TAC mice showed reduced cardiac function and reduced PCr:ATP (16% reduction), but ssTnI TAC hearts maintained cardiac function and energy charge. Contrasting NTG TAC, ssTnI TAC significantly increased glucose oxidation at the expense of palmitate oxidation, preventing the increase in anaplerosis observed in NTG TAC hearts. Elevated glucose oxidation was mediated by a reduction in PDK4 expression, enabling PDH to compete against anaplerotic enzymes for pyruvate carboxylation. </p><p><b><i>Conclusions</i></b>—Expression of a single fetal myofilament protein into adulthood in the ssTnI-TG mouse heart induced downregulation of the gene expression response for PDK to pressure overload. The consequence of elevated pyruvate oxidation in ssTnI during TAC reduced anaplerotic flux, ameliorating inefficiencies in glucose oxidation, with energetic and functional protection against cardiac decompensation.</p> 0 5 2 0 7 no yes CircHF_CIRCHF-2014-001496.xml CLINICAL PERSPECTIVE.docx

CircHF_CIRCHF-2014-001496_fig1.tif

CircHF_CIRCHF-2014-001496_fig2.tif

CircHF_CIRCHF-2014-001496_fig3.tif

CircHF_CIRCHF-2014-001496_fig4.tif

CircHF_CIRCHF-2014-001496_fig5.tif

CircHF_CIRCHF-2014-001496_fig6.tif

CircHF_CIRCHF-2014-001496_fig7.tif

CircHF_CIRCHF-2014-001496_supp2.pdf CircHF_CIRCHF-2014-001496_file1.docx CircHF_CIRCHF-2014-001496_merge.pdf CircHF_CIRCHF-2014-001496_Bi_217788_disclosure.pdf CircHF_CIRCHF-2014-001496_Bi_217788_copyright.pdf CircHF_CIRCHF-2014-001496_Taglieri_99803_disclosure.pdf CircHF_CIRCHF-2014-001496_Taglieri_99803_copyright.pdf CircHF_CIRCHF-2014-001496_Lewandowski_20129_disclosure.pdf CircHF_CIRCHF-2014-001496_Lewandowski_20129_copyright.pdf CircHF_CIRCHF-2014-001496_Carley_168586_disclosure.pdf CircHF_CIRCHF-2014-001496_Carley_168586_copyright.pdf CircHF_CIRCHF-2014-001496_Solaro_23429_disclosure.pdf CircHF_CIRCHF-2014-001496_Solaro_23429_copyright.pdf Please charge authors $70 per page MS has clinical perspective and supplemental PDF Please set the flag 'exportcadmusahafundingtypecodes' with the funding type code of the sources you wish to list. Subject Codes: [140] Energy metabolism [145] Genetically altered mice [15] Hypertrophy [107] Biochemistry and metabolism epicillo