The TRPM4 channel is functionally important for the beneficial cardiac remodeling induced by endurance training

Cardiac hypertrophy (CH) is an adaptive pro- cess 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 molecu- lar 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 cas- cade activated in pathological CH involves the Calcineu- rin-NFAT pathway. It was recently demonstrated that the TRPM4 channel may act as a negative regulator of patho- logical 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 chan- nel in cardiomyocytes after endurance training suggesting a potential role for the channel in physiological CH. We then observed that Trpm4+/+ mice displayed left ventricular Mélanie Gueffier and Justin Zintz have contributed equally to this work. Electronic supplementary material The online version of this article (doi:10.1007/s10974-017-9466-8) contains supplementary material, which is available to authorized users. * Marie Demion marie.demion@inserm.fr 1 Physiologie & Médecine Expérimentale du Cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, 34295 Montpellier cedex 5, France 2 UMR 1149, Université Paris 7, Paris, France 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. Endur- ance training in Trpm4+/+ mice was associated with activa- tion of the classical physiological CH Akt pathway while Trpm4−/− favored the Calcineurin pathway. Calcium stud- ies demonstrated that TRPM4 channel negatively regu- lates 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.