title: A conserved role for phosphatidylinositol 3-kinase but not Akt signaling in mitochondrial adaptations that accompany physiological cardiac hypertrophy.
abstract: Physiological cardiac hypertrophy is associated with mitochondrial adaptations that are characterized by activation of PGC-1alpha and increased fatty acid oxidative (FAO) capacity. It is widely accepted that phosphatidylinositol 3-kinase (PI3K) signaling to Akt1 is required for physiological cardiac growth. However, the signaling pathways that coordinate physiological hypertrophy and metabolic remodeling are incompletely understood. We show here that activation of PI3K is sufficient to increase myocardial FAO capacity and that inhibition of PI3K signaling prevents mitochondrial adaptations in response to physiological hypertrophic stimuli despite increased expression of PGC-1alpha. We also show that activation of the downstream kinase Akt is not required for the mitochondrial adaptations that are secondary to PI3K activation. Thus, in physiological cardiac growth, PI3K is an integrator of cellular growth and metabolic remodeling. Although PI3K signaling to Akt1 is required for cellular growth, Akt-independent pathways mediate the accompanying mitochondrial adaptations.
authors.affiliation: Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.forename: Jaetaek
authors.initials: J
authors.lastname: Kim
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.forename: Heather A
authors.initials: HA
authors.lastname: Theobald
authors.forename: Joseph
authors.initials: J
authors.lastname: Tuinei
authors.forename: Jonathan
authors.initials: J
authors.lastname: Buchanan
authors.forename: Aili
authors.initials: A
authors.lastname: Guo
authors.forename: Vlad G
authors.initials: VG
authors.lastname: Zaha
authors.forename: Don K
authors.initials: DK
authors.lastname: Davis
authors.forename: John C
authors.initials: JC
authors.lastname: Schell
authors.forename: Sihem
authors.initials: S
authors.lastname: Boudina
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wayment
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shioi
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000201:enzymology; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D010805:Physical Conditioning, Animal; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
chemical_list: D005227:Fatty Acids; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta