title: Preventing permeability transition pore opening increases mitochondrial maturation, myocyte differentiation and cardiac function in the neonatal mouse heart.
abstract: BACKGROUND
  In embryonic myocytes, closure of the mitochondrial permeability transition pore (PTP) drives mitochondrial maturation and cardiac myocyte differentiation. Since neonatal cardiac myocytes remain relatively immature, we hypothesized that inducing PTP closure at this age, by inhibiting the PTP regulator, cyclophilin D (CyPD), genetically or with Cyclosporin A (CsA) and NIM811, would increase cardiac function by increasing mitochondrial maturation and myocyte differentiation.
  
  
  METHODS
  Cultured neonatal myocytes or neonatal mice were treated for 5 d with vehicle, CsA or NIM811. Mitochondrial function and structure were measured in vitro. Myocyte differentiation was assessed by immunolabeling for contractile proteins. Cardiac function was determined using echocardiography.
  
  
  RESULTS
  The probability of PTP opening was high in WT neonatal myocytes. Treatment with CsA or NIM811 in vitro increased mitochondrial structural complexity and membrane potential, decreased reactive oxygen species levels, and increased myocyte differentiation. WT mice treated with either CsA or NIM811 in vivo for the first 5 d of life had higher ejection fractions. Deleting CyPD had similar effects as CsA and NIM811 on all parameters.
  
  
  CONCLUSIONS
  It may be feasible to inhibit the PTP using available drugs to increase mitochondrial maturation, myocyte differentiation, and cardiac function in neonates.
authors.affiliation: Current affiliation: Department of Pediatrics, Benefits Health System, Great Falls, Montana.|Department of Pediatrics, University of Rochester Medical Center, Rochester, New York.
authors.forename: Jayson V
authors.initials: JV
authors.lastname: Lingan
authors.affiliation: Department of Pediatrics, University of Rochester Medical Center, Rochester, New York.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Alanzalon
authors.affiliation: Department of Pediatrics, University of Rochester Medical Center, Rochester, New York.|Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York.|Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York.
authors.forename: George A
authors.initials: GA
authors.lastname: Porter
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002478:Cells, Cultured; D006334:Heart Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000166:cytology*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore