Mechanosensory Decline in Embryonically Derived Cardiac Macrophages Drives Age-Associated Myocardial Dysfunction via Loss of Piezo1

Background and Aims: Cardiac aging is characterized by a progressive loss of resilience, yet the cellular mechanisms linking immune cell dysfunction to myocardial decline remain poorly understood. This study aimed to identify how aging affects resident cardiac macrophages of embryonic origin and to define molecular determinants of their functional decline.
Methods: We combined single-cell and single-nucleus RNA sequencing of young and aged murine hearts (n=46) with functional and imaging assays to dissect age-associated changes in cardiac macrophages. Conditional myeloid-specific deletion models were employed to assess the role of the mechanosensitive ion channel Piezo1 in macrophage function and cardiac performance. Phagocytic and lysosomal activity was analyzed transcriptionally and through bone marrow–derived macrophage assays.
Results: Multi-omic profiling revealed myeloid-driven transcriptional senescence marked by impaired efferocytosis, mitochondrial dysfunction, and inflammatory reprogramming. Among all cardiac macrophage subsets, embryonically derived resident macrophages showed the strongest transcriptional changes with aging, including a pronounced decline in phagocytic capacity. Aging was associated with a consistent decline in Piezo1 expression across cardiac macrophage subsets, linking reduced mechanosensation to activation of senescence-associated gene programs. Loss of mechanosensing through Piezo1 deletion impaired phagocytosis and lysosomal activity, highlighting mechanotransduction as a key process maintaining clearance capacity in aging macrophages. Myeloid-specific Piezo1 deletion in vivo resulted in progressive cardiac dysfunction with reduced fractional shortening and ejection fraction. Transcriptomic analyses showed early and persistent impairment of clearance pathways in Piezo1-deficient macrophages, while cardiomyocytes exhibited secondary stress responses and mitochondrial damage. Impaired phagocytic function was further validated in vitro using bone marrow–derived macrophage assays, which confirmed reduced clearance of damaged cardiomyocytes by Piezo1-deficient macrophages.
Conclusion: Piezo1 acts as a mechanosensory checkpoint preserving macrophage clearance capacity and immune–cardiac balance. Its decline in embryonically derived resident macrophages underlies their loss of phagocytic function and contributes to age-associated cardiac dysfunction.
Keywords: Cardiac aging, Macrophages, Mechanosensation, Piezo1, Senescence, Phagocytosis