title: Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts.
abstract: Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway. To test whether PGC-1α is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1α (∼3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1α overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice.
authors.affiliation: Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington.
authors.forename: Georgios
authors.initials: G
authors.lastname: Karamanlidis
authors.affiliation: Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington.
authors.forename: Lorena
authors.initials: L
authors.lastname: Garcia-Menendez
authors.affiliation: Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Kolwicz
authors.affiliation: Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington.
authors.forename: Chi Fung
authors.initials: CF
authors.lastname: Lee
authors.affiliation: Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington rongtian@u.washington.edu.
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
mesh_terms: D000818:Animals; D002950:Citrate (si)-Synthase / Q000235:genetics / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D063269:Mitochondrial Turnover; D009200:Myocardial Contraction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology
chemical_list: D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D002950:Citrate (si)-Synthase
keywords: cardiac hypertrophy; energetics; heart failure; mitochondrial biogenesis; peroxisome proliferator-activated receptor-γ coactivator 1α