Transient Receptor Potential (TRP) channels, in particular the TRPC subclass, have been shown as pathological cardiac hypertrophy (CH) regulators probably via the Cn-NFAT pathway activation. By contrast, the physiological CH depends on the IGF-1-PI3K-Akt pathway activation. The TRPM4 channel is a Ca²⁺-activated channel weakly expressed at the ventricular level while it seems to be a negative regulator of TRPC channel and could be also re-expressed in ventricle during pathological CH. Our purpose was to determine whether TRPM4 channel could be involved in physiological CH and what are the consequences on Ca²⁺ homeostasis.

To induce physiological CH, mice were assigned to sedentary or treadmill running (TR). Echocardiograms demonstrated that mice displayed morpho-functional cardiac adaptations associated with an increase of P-Akt/Akt protein ratio validating physiological CH in TR mice. TRPM4 channel mRNA was increased in the ventricle of trained mice, associated with protein detection. Using the patch-clamp technique, we unmasked a Ca²⁺-activated non-selective cationic current, which shares the eletrophysiological properties of those recorded for the TRPM4 channel. We use of a selective TRPM4 inhibitor, 9-Phenanthrol, to blunt TRPM4 channel activity during the excitation-contraction coupling (ECC) recording under Isoproterenol stimulation, a β agonist. Treated cardiomyocytes displayed a diastolic [Ca²⁺] and maximal Ca²⁺ amplitude decreased, underlying TRPM4 channel involvement in ECC.

This study provides the first evidence of functional TRPM4 channel re-expression during physiological CH and its potential role in Ca²⁺ homeostasis.