Deletion of PIEZO1 in adult cardiomyocytes accelerates cardiac aging and causes premature death

Background:

Blood flows through the cardiovascular system in a pulsatile fashion, exerting mechanical force on the cells that make up its tissues and organs. To ensure adaptation to this flow, cells need to be able to sense these mechanical cues. One of the ways in which cells can sense mechanical forces is PIEZO1, a channel protein sensitive to mechanical deformation. PIEZO1 is expressed in many different cell types, including cardiomyocytes. It is involved in the hypertrophy observed in response to pressure overload, causing an increase in tissue size due to an increase in the size of individual cells. This can occur via the stimulation of downstream signaling factors such as Ca²⁺/Calmodulin-dependent kinase II (CaMKII), an enzyme that catalyzes the addition of a phosphate group to a target molecule.

To evaluate the role of PIEZO1 in baseline cardiomyocyte function in aging mice, the authors studied mice that carry a conditional knockout (cKO) of the piezo1 gene. Piezo1 cKO in this model system is induced only in cardiomyocytes and only after administration of tamoxifen. Upon induction, Cre recombinase, which is under the transcriptional control of the aMHCgene, is expressed, removing piezo1 from the cardiomyocyte genome (Yu et al., 2025).

Key findings of the study:

1. Mice with the Piezo1 cKO experience premature death, starting 72 weeks after treatment with tamoxifen. Critically, this limited the authors’ ability to investigate more long-term changes in function from a planned 24 months to 18 months post-tamoxifen.
2. Aging is linked with increased expression of genes related to the Senescence-Associated Secretory Phenotype (SASP) (IL1β, IL6, TGFβ, TNFα) and increased expression of p53, p16, p21, all of which were elevated in left ventricular tissue of aged Piezo1 cKO mice. The authors attribute the reduced survival rates in the Piezo1 cKO mice to this observed cardiac senescence.
3. Cellular hypertrophy of the heart muscle can occur because of the normal aging process. In this study, this hypertrophic response was blunted; not only was the heart weight and individual chamber weight reduced in the aged Piezo1 cKO mice group, but individual cardiomyocyte size was affected as well, with cells exhibiting a smaller surface area (reduction by ~ 13%). This was caused by reduced activation of the signal transduction pathway employing CaMKII, as levels of phosphorylated CaMKII were reduced as well.
4. Cardiac relaxation times were increased in PIEZO1 cKO mice, resulting in diastolic dysfunction. The authors linked the dysregulation of Ca²⁺ handling with the dysregulation in various Ca²⁺-handling proteins such as phospholamban (PLN), SERCA2α and the Na⁺/Ca²⁺ exchanger protein. There was also a reduction in heart rate (bradycardia), which reduced cardiac output (CO) by ~ 30% compared to controls.
5. Fibrosis was more pronounced in the aged Piezo1 KO mice group, especially in the right atrium (RA), as seen with Masson trichrome staining. Expression of the Collagen III gene (Col3α1), a marker for myocardial fibrosis, was increased as well. In young control groups, highest expression of Piezo1 and ANP was found in tissue sections from the RA. ANP is normally secreted in response to mechanical stretch and can generally affect the degree of cardiac fibrosis. In affected hearts, both Piezo1 and ANP expression were reduced, especially in the RA. Moreover, ANP secretion in living animals was also affected, as acute increases in intravascular volume lead only to modest increases in ANP (Yu et al., 2025).

Why this work is interesting:

Other studies evaluating the effect of Piezo1 deletion report a phenotype characterized by dilatation (dilated cardiomyopathy), observed in hearts still in the process of development (Jiang et al., 2021). This study, on the other hand, evaluates Piezo1 deletion at a different timepoint, after cardiac development is complete (adult), during which time no evidence of cardiac dilatation is observed. This demonstrates the different ways in which PIEZO1 and its absence, can affect baseline cardiac function at different time points in the life cycle of an animal (Yu et al., 2025). Cardiac aging can be clinically observed via echocardiography as a stiff heart with diastolic dysfunction, as we often see in patients that are part of our clinical research projects. On a cellular and tissue level this can be, in part, due to the hypertrophy observed during aging, which is really the normal cellular response that occurs in aging cardiomyocytes. Absence of PIEZO1 would abolish this normal hypertrophic response while also having additional detrimental effects on the phenotype (reduced CO, disturbances in rate or rhythm, increase in tissue senescence, increased fibrosis), despite the apparent ‘improvement’ in the hypertrophy.

Open questions to the authors about their work:

1. In this study, the progressive effects on heart rate are attributed to the presence of cardiac fibrosis, which is more pronounced in the RA. How is the fibrotic material distributed in the tissue sections of the RA, especially with regard to the sinoatrial (SA) node, i.e., is fibrosis more pronounced close or around the SA node?
2. Some studies in animal models associate cardiac fibrosis in the atria with the development of atrial fibrillation (AF) (Abed et al., 2013) (Adam et al., 2012), although in these studies a different intervention is used to stimulate fibrosis. Other studies examining the effect of prolonged PIEZO1 activation in zebrafish have also reported bradycardia (as is the case with this study), along with increases in the QT interval, i.e., the interval measured from the start of the Q wave to the end of the T wave on the electrocardiogram (corresponds to the time needed for ventricular depolarization and repolarization) and AF. However, the latter two are observed in immature hearts (Rolland et al., 2023). Do you think there are any specific parameters in this study that only result in bradycardia? Could the developmental timepoint at which the heart is studied (embryonic or adult) play a role? Do you think the type of animal model used can lead to differences in the type or range of arrhythmic responses observed?

References:

1. Abed, H.S., Samuel, C.S., Lau, D.H., Kelly, D.J., Royce, S.G., Alasady, M., Mahajan, R., Kuklik, P., Zhang, Y., Brooks, A.G., Nelson, A.J., Worthley, S.G., Abhayaratna, W.P., Kalman, J.M., Wittert, G.A., Sanders, P., 2013. Obesity results in progressive atrial structural and electrical remodeling: Implications for atrial fibrillation. Heart Rhythm 10, 90–100. https://doi.org/10.1016/j.hrthm.2012.08.043
2. Adam, O., Löhfelm, B., Thum, T., Gupta, S.K., Puhl, S.-L., Schäfers, H.-J., Böhm, M., Laufs, U., 2012. Role of miR-21 in the pathogenesis of atrial fibrosis. Basic Res. Cardiol. 107, 278. https://doi.org/10.1007/s00395-012-0278-0
3. Jiang, F., Yin, K., Wu, K., Zhang, M., Wang, S., Cheng, H., Zhou, Z., Xiao, B., 2021. The mechanosensitive Piezo1 channel mediates heart mechano-chemo transduction. Nat. Commun. 12, 869. https://doi.org/10.1038/s41467-021-21178-4
4. Rolland, L., Torrente, A.G., Bourinet, E., Maskini, D., Drouard, A., Chevalier, P., Jopling, C., Faucherre, A., 2023. Prolonged Piezo1 Activation Induces Cardiac Arrhythmia. Int. J. Mol. Sci. 24, 6720. https://doi.org/10.3390/ijms24076720
5. Yu, Z.-Y., Guo, Y., Kesteven, S., Cheng, D., Lei, H., Wu, J., Nadar, E., Macdonald, P., Xaymardan, M., Cox, C.D., Feneley, M.P., Martinac, B., 2025. Deletion of PIEZO1 in adult cardiomyocytes accelerates cardiac aging and causes premature death. https://doi.org/10.1101/2025.01.20.633994

Tags: aging, animal, biology, cardiovascular, hypertrophy, model

(No Ratings Yet)