1. Reviewer #3 (Public Review):

    The goal of this study was to test the hypothesis that the calcium-activated TRPM4 channel regulates left ventricular (LV) hypertrophy which occurs after pressure overload. The authors use the transaortic constriction model (TAC) which represents a common and well-validated model of LV hypertrophy and of heart failure. Typical LV pressure overload models range from relatively mild constriction using a 25 gauge needle to more severe constriction with a 27 gauge needle. In this study the authors demonstrate that two weeks of pressure overload with a 25 gauge needle in mice produces LV hypertrophy, increased fibrosis, and a pattern of fetal gene re-expression which marks the pathological hypertrophy phenotype. This phenotype precedes overt cardiac dysfunction, in the sense that the functional measures the authors used did not worsen after two weeks in TAC mice, compared to sham-treated controls. These results reproduce prior observations in this model.

    The authors next apply the 2 week TAC model to previously-generated mice with cardiac myocyte-restricted deletion of the TRPM4 channel. They demonstrate that deletion of TRPM4 generates a protective response, in that despite the same degree of pressure overload, the TRPM4 cardiac myocyte-specific deletion mice develop less LV hypertrophy, less LV fibrosis, and less fetal gene re-expression. Thus the authors successfully demonstrate that deletion of TRPM4 reduces pressure overload-induced LV hypertrophy. This suggests that TRPM4 normally promotes pathological LV hypertrophy after pressure overload.

    While this work convincingly demonstrates that TRPM4 deletion from the cardiac myocyte leads to reduced pressure overload-induced LV hypertrophy, the study does not prove the intracellular signaling mechanisms which mediate this effect. The authors' model is that: 1) neurohormonal signals for pressure overload predominantly induce LV hypertrophy through a calcineurin pathway leading to nuclear import of NFAT; and 2) mechanical stretch (such as induced by TAC) predominantly acts through the intracellular kinase CaMKII which then phosphorylates histone deacetylase 4, thus promoting HDAC4 nuclear import. The study does not prove whether any of these signaling components are necessary or sufficient for the effects of TRPM4 on LV hypertrophy in vivo.

    As a whole this work will be of interest to the larger scientific community for several reasons. First, in response to a different model of pathologic LV hypertrophy, the angiotensin II infusion model, the TRPM4 cardiac myocyte deletion mice actually develop increased, rather than decreased, LV hypertrophy. Thus the combined observations that TRPM4 deletion suppresses pressure overload LV hypertrophy by TAC, but augments neurohormonal hypertrophy by angiotensin administration support the important concept that different stimuli of hypertrophy likely act through and are regulated by different signaling pathways. Second, as a membrane associated ion channel, TRPM4 might be a potential drug target especially in patients with pressure overload-induced pathological hypertrophy.

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  2. Reviewer #2 (Public Review):

    The manuscript by Guo et al. focuses on the involvement of TRPM4 channel in the development of pressure overload-induced cardiac hypertrophy. They show that TRPM4 expression, in both mRNA and protein, was downregulated in response to left ventricular pressure overload in wild type mice. They demonstrate that a reduction in TRPM4 expression in cardiomyocytes reduces the hypertrophic response to pressure overload due to transverse aortic arch constriction. Furthermore, they show that activation of CaMKIIδ-HDAC4-MEF2A pathway is reduced in mice with cardiomyocyte-specific, conditional deletion of Trpm4. Originally, TRPM4 channel was well known for its association with cardiomyocyte action potential formation and arrhythmia, but this study is very interesting in that it clarified the association of TRPM4 channel with the mechanotransduction mechanism of ventricular pressure overload. Their work may lead to the development of treatment strategies for hypertensive heart disease.

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  3. Reviewer #1 (Public Review):

    This study indicated that transient receptor potential channel subfamily melastatin 4 (TRPM4), a Ca2+ and voltage activated non-selective monovalent cation channel, might contribute to pressure overload-induced cardiac hypertrophy, although not through direct mechanical stretch-related activation. TRPM4 could possibly activate several Calmodulin (CaM)-related downstream signaling pathways, resulting in cardiac hypertrophy. However, the important question of what is mechanistic link of mechanical stretch and activation of TRPM4 ion channel is left unanswered.

    Strength: The experiments are well designed with reliable data presented. The utilization of TAC mice model presented in this study was backed with proper reasoning with appropriate proof-of-concept results, especially concerning the 2-day TAC protocol.

    Weakness: Trpm4cKO mice have been previously studied in another cardiac hypertrophy model by using angiotensin II, which lessened the novelty value in the findings of this study. Furthermore, the data presented in this paper were inadequate to fully answer their research questions and further in vivo and in vitro studies are needed to confirm the mechanism that can explain the phenomenon seen in the results.

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  4. Evaluation Summary:

    In this work, the authors subjected mice with cardiomyocyte-specific deletion of ion channel TRPM4 to transverse aortic constriction-induced pressure overload, which is a well-validated model for heart failure. The study showed that cell-specific loss of TRPM4 in cardiomyocytes could protect against pathological left ventricular hypertrophy which is associated with an attenuation of pathological changes in the expression several genes that become dysregulated during the development pathological hypertrophy. These findings are likely to contribute to understanding of pressure overload-induced hypertrophy heart disease and the pathophysiology of heart failure.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

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