title: Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor-γ coactivators PGC1α and PGC1β modulate mitochondrial biogenesis and energy homeostasis. The function of these transcriptional coactivators is impaired in obesity, insulin resistance, and type 2 diabetes. We searched for transcriptomic, lipidomic, and electrophysiological alterations in PGC1β(-/-) hearts potentially associated with increased arrhythmic risk in metabolic diseases.
  
  
  RESULTS
  Microarray analysis in mouse PGC1β(-/-) hearts confirmed down-regulation of genes related to oxidative phosphorylation and the electron transport chain and up-regulation of hypertrophy- and hypoxia-related genes. Lipidomic analysis showed increased levels of the pro-arrhythmic and pro-inflammatory lipid, lysophosphatidylcholine. PGC1β(-/-) mouse electrocardiograms showed irregular heartbeats and an increased incidence of polymorphic ventricular tachycardia following isoprenaline infusion. Langendorff-perfused PGC1β(-/-) hearts showed action potential alternans, early after-depolarizations, and ventricular tachycardia. PGC1β(-/-) ventricular myocytes showed oscillatory resting potentials, action potentials with early and delayed after-depolarizations, and burst firing during sustained current injection. They showed abnormal diastolic Ca(2+) transients, whose amplitude and frequency were increased by isoprenaline, and Ca(2+) currents with negatively shifted inactivation characteristics, with increased window currents despite unaltered levels of CACNA1C RNA transcripts. Inwardly and outward rectifying K(+) currents were all increased. Quantitiative RT-PCR demonstrated increased SCN5A, KCNA5, RYR2, and Ca(2+)-calmodulin dependent protein kinase II expression.
  
  
  CONCLUSIONS
  PGC1β(-/-) hearts showed a lysophospholipid-induced cardiac lipotoxicity and impaired bioenergetics accompanied by an ion channel remodelling and altered Ca(2+) homeostasis, converging to produce a ventricular arrhythmic phenotype particularly during adrenergic stress. This could contribute to the increased cardiac mortality associated with both metabolic and cardiac disease attributable to lysophospholipid accumulation.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. isg22@cam.ac.uk
authors.forename: Iman S
authors.initials: IS
authors.lastname: Gurung
authors.forename: Gema
authors.initials: G
authors.lastname: Medina-Gomez
authors.forename: Adrienn
authors.initials: A
authors.lastname: Kis
authors.forename: Michael
authors.initials: M
authors.lastname: Baker
authors.forename: Vidya
authors.initials: V
authors.lastname: Velagapudi
authors.forename: Sudeshna Guha
authors.initials: SG
authors.lastname: Neogi
authors.forename: Mark
authors.initials: M
authors.lastname: Campbell
authors.forename: Sergio
authors.initials: S
authors.lastname: Rodriguez-Cuenca
authors.forename: Christopher
authors.initials: C
authors.lastname: Lelliott
authors.forename: Ian
authors.initials: I
authors.lastname: McFarlane
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D006706:Homeostasis; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D016601:RNA-Binding Proteins; D059467:Transcriptome
chemical_list: D002352:Carrier Proteins; D008246:Lysophospholipids; C455622:PPARGC1B protein, human; D016601:RNA-Binding Proteins; D011188:Potassium; D002118:Calcium