title: Exercise triggers ARVC phenotype in mice expressing a disease-causing mutated version of human plakophilin-2.
abstract: BACKGROUND
  Exercise has been proposed as a trigger for arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotype manifestation; however, research is hampered by the limited availability of animal models in which disease-associated mutations can be tested.
  
  
  OBJECTIVE
  This study evaluated the impact of exercise on ARVC cardiac manifestations in mice after adeno-associated virus (AAV)-mediated gene delivery of mutant human PKP2, which encodes the desmosomal protein plakophilin-2.
  
  
  METHODS
  We developed a new model of cardiac tissue-specific transgenic-like mice on the basis of AAV gene transfer to test the potential of a combination of a human PKP2 mutation and endurance training to trigger an ARVC-like phenotype.
  
  
  RESULTS
  Stable cardiac expression of mutant PKP2 (c.2203C>T), encoding the R735X mutant protein, was achieved 4 weeks after a single AAV9-R735X intravenous injection. High-field cardiac magnetic resonance over a 10-month postinfection follow-up did not detect an overt right ventricular (RV) phenotype in nonexercised (sedentary) mice. In contrast, endurance exercise training (initiated 2 weeks after AAV9-R735X injection) resulted in clear RV dysfunction that resembled the ARVC phenotype (impaired global RV systolic function and RV regional wall motion abnormalities on cardiac magnetic resonance). At the histological level, RV samples from endurance-trained R735X-infected mice displayed connexin 43 delocalization at intercardiomyocyte gap junctions, a change not observed in sedentary mice.
  
  
  CONCLUSIONS
  The introduction of the PKP2 R735X mutation into mice resulted in an exercise-dependent ARVC phenotype. The R735X mutation appears to function as a dominant-negative variant. This novel system for AAV-mediated introduction of a mutation into wild-type mice has broad potential for study of the implication of diverse mutations in complex cardiomyopathies.
authors: Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: Francisco M
authors: FM
authors: Cruz
authors: Epidemiology, Atherothrombosis and Imaging Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: David
authors: D
authors: Sanz-Rosa
authors: Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: Marta
authors: M
authors: Roche-Molina
authors: Epidemiology, Atherothrombosis and Imaging Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: Jaime
authors: J
authors: García-Prieto
authors: Epidemiology, Atherothrombosis and Imaging Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: José M
authors: JM
authors: García-Ruiz
authors: Epidemiology, Atherothrombosis and Imaging Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: Gonzalo
authors: G
authors: Pizarro
authors: Epidemiology, Atherothrombosis and Imaging Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: Luis J
authors: LJ
authors: Jiménez-Borreguero
authors: Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: Miguel
authors: M
authors: Torres
authors: Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: Antonio
authors: A
authors: Bernad
authors: Advanced Imaging Unit, Epidemiology, Atherothrombosis and Imaging Department, Ciber de Enfermedades Respiratorias and Universidad Complutense, Madrid, Spain.
authors: Jesús
authors: J
authors: Ruíz-Cabello
authors: Epidemiology, Atherothrombosis and Imaging Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York.
authors: Valentín
authors: V
authors: Fuster
authors: Epidemiology, Atherothrombosis and Imaging Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; Cardiovascular Institute, Hospital Clínico San Carlos, Madrid, Spain. Electronic address: bibanez@cnic.es.
authors: Borja
authors: B
authors: Ibáñez
authors: Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. Electronic address: jabernal@cnic.es.
authors: Juan A
authors: JA
authors: Bernal
mesh_terms: D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D010805:Physical Conditioning, Animal / Q000379:methods / Q000502:physiology*; D051191:Plakophilins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C495337:PKP2 protein, human; D051191:Plakophilins
keywords: ARVC; arrhythmia; dysplasia; mutation; transgenic mice