Genetic background influences expression and function of the cation channel TRPM4 in the mouse heart

Abstract

Transient receptor potential melastatin 4 (TRPM4) cation channels act in cardiomyocytes as a negative modulator of the L-type Ca2+ current. Ubiquitous Trpm4 deletion in mice leads to an increased β-adrenergic inotropy in healthy mice as well as after myocardial infarction. In this study, we set out to investigate cardiac inotropy in mice with cardiomyocyte-specific Trpm4 deletion. The results guided us to investigate the relevance of TRPM4 for catecholamine-evoked Ca2+ signaling in cardiomyocytes and inotropy in vivo in TRPM4-deficient mouse models of different genetic background. Cardiac hemodynamics were investigated using pressure–volume analysis. Surprisingly, an increased β-adrenergic inotropy was observed in global TRPM4-deficient mice on a 129SvJ genetic background, but the inotropic response was unaltered in mice with global and cardiomyocyte-specific TRPM4 deletion on the C57Bl/6N background. We found that the expression of TRPM4 proteins is about 78 ± 10% higher in wild-type mice on the 129SvJ versus C57Bl/6N background. In accordance with contractility measurements, our analysis of the intracellular Ca2+ transients revealed an increase in ISO-evoked Ca2+ rise in Trpm4-deficient cardiomyocytes of the 129SvJ strain, but not of the C57Bl/6N strain. No significant differences were observed between the two mouse strains in the expression of other regulators of cardiomyocyte Ca2+ homeostasis. We conclude that the relevance of TRPM4 for cardiac contractility depends on homeostatic TRPM4 expression levels or the genetic endowment in different mouse strains as well as on the health/disease status. Therefore, the concept of inhibiting TRPM4 channels to improve cardiac contractility needs to be carefully explored in specific strains and species and prospectively in different genetically diverse populations of patients.

Development of an AAV9-RNAi-mediated silencing strategy to abrogate TRPM4 expression in the adult heart

“…In vitro studies on isolated cardiomyocytes indicated that TRPM4 deficiency is associated with a faster repolarization of the action potential and an increased Ca 2+ influx via L-type channels with isoproterenol stimulation [ 23 ]. Recently, we could show that the increased ISO-evoked inotropy and elevated Ca 2+ transient can only be observed in TRPM4-deficeint mice on the 129SvJ genetic background and the TRPM4 protein expression level is about 80% higher in wild-type 129SvJ mice than in mice with C57B/6N background [ 26 ]. The results of this study indicate that the relevance of TRPM4 for cardiac contractility depends on homeostatic TRPM4 expression levels or the genetic background of different mouse strains.…”

Mapping the expression of transient receptor potential channels across murine placental development

“…Importantly, strain-dependent differences were observed in that the overall placental expression of Trpm4 was higher in the mixed BL6/129S background. Although no subfertile phenotype is reported for TRPM4 knockout mice so far with either 129/Svj or C57BL/6J background, it is interesting to note that strain-specific cardiac phenotypes were observed [58][59][60][61][62]. While the entire placental Trpm4 levels were above threshold, spatial FISH expression studies revealed very low expression in the placenta.…”

Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 2: TRPM4 in Health and Disease

“…The reason for this difference can be the use of Wistar (or Wistar-Kyoto) rats in previous papers [43,147] while Sprague-Dawley rats have been used more recently [44,127]. Indeed, at least in mice, TRPM4 protein expression was about 80% higher in animals with a 129SvJ background versus a C57Bl/6N background [152]. Moreover, on the functional level, increased β-adrenergic inotropy was detected in global TRPM4-deficient 129SvJ mice, but the inotropic response was unaltered in C57Bl/6N mice with both global and cardiomyocyte-specific TRPM4 deletion [152].…”