title: The TRPM4 channel is functionally important for the beneficial cardiac remodeling induced by endurance training.
abstract: Cardiac hypertrophy (CH) is an adaptive process that exists in two distinct forms and allows the heart to adequately respond to an organism's needs. The first form of CH is physiological, adaptive and reversible. The second is pathological, irreversible and associated with fibrosis and cardiomyocyte death. CH involves multiple molecular mechanisms that are still not completely defined but it is now accepted that physiological CH is associated more with the PI3-K/Akt pathway while the main signaling cascade activated in pathological CH involves the Calcineurin-NFAT pathway. It was recently demonstrated that the TRPM4 channel may act as a negative regulator of pathological CH by regulating calcium entry and thus the Cn-NFAT pathway. In this study, we examined if the TRPM4 channel is involved in the physiological CH process. We evaluated the effects of 4 weeks endurance training on the hearts of Trpm4+/+and Trpm4-/-mice. We identified an elevated functional expression of the TRPM4 channel in cardiomyocytes after endurance training suggesting a potential role for the channel in physiological CH. We then observed that Trpm4+/+mice displayed left ventricular hypertrophy after endurance training associated with enhanced cardiac function. By contrast, Trpm4-/-mice did not develop these adaptions. While Trpm4-/-mice did not develop gross cardiac hypertrophy, the cardiomyocyte surface area was larger and associated with an increase of Tunel positive cells. Endurance training in Trpm4+/+mice did not increase DNA fragmentation in the heart. Endurance training in Trpm4+/+mice was associated with activation of the classical physiological CH Akt pathway while Trpm4-/-favored the Calcineurin pathway. Calcium studies demonstrated that TRPM4 channel negatively regulates calcium entry providing support for activation of the Cn-NFAT pathway in Trpm4-/-mice. In conclusion, we provide evidence for the functional expression of TRPM4 channel in response to endurance training. This expression may help to maintain the balance between physiological and pathological hypertrophy.
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Gueffier
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France.
authors.forename: Justin
authors.initials: J
authors.lastname: Zintz
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France.
authors.forename: Karen
authors.initials: K
authors.lastname: Lambert
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France.
authors.forename: Amanda
authors.initials: A
authors.lastname: Finan
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Aimond
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France.
authors.forename: Nourdine
authors.initials: N
authors.lastname: Chakouri
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hédon
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Granier
authors.affiliation: UMR 1149, Université Paris 7, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Launay
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.affiliation: Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295, Montpellier cedex 5, France. marie.demion@inserm.fr.
authors.forename: Marie
authors.identifier: 0000-0003-4777-0654
authors.initials: M
authors.lastname: Demion
mesh_terms: D000818:Animals; D064752:Atrial Remodeling / Q000502:physiology*; D006332:Cardiomegaly; D008297:Male; D051379:Mice; D010807:Physical Endurance / Q000502:physiology*; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse
keywords: Calcium entry; Cardiac hypertrophy; Endurance training; TRPM4 channel