2026-06-14T03:39:17Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/268132025-12-18T13:01:53Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Wang, Ping author Ahmed, Mahmoud Salama author Nguyen, Ngoc Uyen Nhi author Menendez-Montes, Ivan author Hsu, Ching-Cheng author Farag, Ayman B author Thet, Suwannee author Lam, Nicholas T author Wansapura, Janaka P author Crossley, Eric author Ma, Ning author Zhao, Shane Rui author Zhang, Tiejun author Morimoto, Sachio author Singh, Rohit author Elhelaly, Waleed author Tassin, Tara C author Cardoso, Alisson C author Williams, Noelle S author Pointer, Hayley L author Elliott, David A author McNamara, James W author Watt, Kevin I author Porrello, Enzo R author Sadayappan, Sakthivel author Sadek, Hesham A author 2025-02-17 Dilated cardiomyopathy (DCM) due to genetic disorders results in decreased myocardial contractility, leading to high morbidity and mortality rates. There are several therapeutic challenges in treating DCM, including poor understanding of the underlying mechanism of impaired myocardial contractility and the difficulty of developing targeted therapies to reverse mutation-specific pathologies. In this report, we focused on K210del, a DCM-causing mutation, due to 3-nucleotide deletion of sarcomeric troponin T (TnnT), resulting in loss of Lysine210. We resolved the crystal structure of the troponin complex carrying the K210del mutation. K210del induced an allosteric shift in the troponin complex resulting in distortion of activation Ca2+-binding domain of troponin C (TnnC) at S69, resulting in calcium discoordination. Next, we adopted a structure-based drug repurposing approach to identify bisphosphonate risedronate as a potential structural corrector for the mutant troponin complex. Cocrystallization of risedronate with the mutant troponin complex restored the normal configuration of S69 and calcium coordination. Risedronate normalized force generation in K210del patient-induced pluripotent stem cell-derived (iPSC-derived) cardiomyocytes and improved calcium sensitivity in skinned papillary muscles isolated from K210del mice. Systemic administration of risedronate to K210del mice normalized left ventricular ejection fraction. Collectively, these results identify the structural basis for decreased calcium sensitivity in K210del and highlight structural and phenotypic correction as a potential therapeutic strategy in genetic cardiomyopathies. J Clin Invest. 2025 Feb 17;135(4):e174081. Journal of Clinical Investigation 39959972 https://hdl.handle.net/20.500.12105/26813 Cardiology Genetic diseases Heart failure An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models.