2026/03/23 by Michael Ibrahim, Vasiliki Courelli, Lan Cheng +7 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Cardiac Fibrosis and Remodeling #Cardiomyopathy and Myosin Studies #Cellular Mechanics and Interactions
paper · doi:10.1016/j.jmccpl.2026.100843
openalex publication_date 2026/03/23 · openalex created_date 2026/03/24 · openalex updated_date 2026/07/23
T-tubules are invaginations of the cardiomyocyte sarcolemma, essential for excitation–contraction coupling and calcium-induced calcium release. Disruption of T-tubule structure contributes to contractile dysfunction in heart failure, yet the mechanisms driving this remodeling remain poorly understood. Here, we investigated whether mechanical load alone, independent of neurohormonal signals and extracellular matrix cues, is sufficient to induce pathological remodeling of T-tubules in isolated cardiomyocytes. Using a magnetorheological elastomer (MRE) culture system with tunable stiffness, we subjected adult rat cardiomyocytes to mechanical microenvironments spanning that of healthy (10 kPa) and diseased (50 kPa) myocardium. We assessed Ca 2+ -handling, T-tubule architecture, and the localization of key structural and functional proteins, as well as evaluated the role of the microtubule cytoskeleton using nocodazole-mediated depolymerization. We found that pathological substrate stiffness impaired Ca 2+ -transients, increased Ca 2+ -release dyssynchrony, and disrupted T-tubule organization, causing a shift from transverse to longitudinal orientation. We found no differences in key T-tubule total protein levels between experimental groups but observed spatial reorganization of TCAP in response to substrate stiffening. Microtubule depolymerization with nocodazole prevented pathological t-tubule remodeling, suggesting that microtubules act as mechanotransducers that orchestrate subcellular reorganization in response to mechanical cues. Our findings highlight the intrinsic ability of cardiomyocytes to remodel in response to mechanical load in the form of extracellular mechanical stiffness, in the absence of external hormonal influences, other cell types, the extracellular matrix, and other compensatory systemic responses, and that this is largely mediated by the microtubular network.