Promoting Autophagy Mitigates Stress‐Induced Remodeling in Patient iPSC‐CMs with the Phospholamban R9C Mutation
Year: 2025
Type: article
Abstract: Phospholamban (PLN) is a key regulator of adrenergic signaling and calcium homeostasis in cardiomyocytes. The PLN R9C mutation causes early-onset dilated cardiomyopathy (DCM) and premature death, yet the mechanisms underlying its pathogenic remodeling remain unclear. In this study, patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harboring the PLN R9C and their isogenic corrected controls are generated to investigate the molecular and functional consequences of the mutation. At baseline, PLN R9C iPSC-CMs exhibit near-normal calcium handling but blunt β-adrenergic signaling and slightly enhanced contractility. Under functional stress induced by a pro-maturation medium, mutant cells develop marked sarcomere disarray, impaired calcium handling, elevated diastolic calcium, and reduced contractile force, whereas corrected cells show adaptive improvement. Transcriptomic and biochemical analyses reveal activation of proteostasis pathways but accumulation of PLN pentamers and impaired autophagic flux, suggesting that autophagic overload contributes to functional remodeling. Treatment with the autophagy activator metformin mitigates sarcomere disorganization, restores calcium homeostasis, and improves contractility in patient-derived iPSC-CMs. These findings are further validated in wild-type and genome-engineered PLN R9C iPSC-CMs. Collectively, the study demonstrates that PLN R9C drives stress-induced pathological remodeling by disrupting proteostasis, and that enhancing autophagic flux offers a promising therapeutic strategy for DCM patients carrying PLN mutations.
Source: Advanced Science
Authors: Qi Yu, Yawei Shen, Robert J. Barndt, Karim Sallam, Ying Tang, Cameron E. Brown, Xiao Li, Stephen Y. Chan, Joseph C. Wu, Qing Liu, Haodi Wu
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,730
Awards: G1122492105, G1373307971, G2070399738, Epigenetic regulation of PDE signaling in dilated cardiomyopathy, G3802787806, G4152001956, G4474944004, G5366160927, Bigfoot Spectral Cell Sorter, Defining the systems biology of the vascular matrix in pulmonary hypertension, Request for transmission electron microscope for the University of Pittsburgh, Frataxin deficiency as a cause of endothelial senescence in multiple subtypes of pulmonary hypertension, G8206972408, Genetic and hypoxic control of a lncRNA axis orchestrates endothelial reprogramming in pulmonary hypertension, Multiscale Systems to Elucidate Susceptibility and Cardioprotective Mechanisms in Cardio-oncology, Human iPSCs for Elucidating Intercellular Crosstalk Signaling in Dilated Cardiomyopathy, The non-canonical roles of NIPBL in cardiomyocytes, COBRE in Human Genetics, Elucidating Mechanism of Cardiac Fibrosis with Cell Village of Pooled Human iPSCs, An endothelial-fibroblast axis connecting senescence to amino acid metabolism for control of vascular stiffness in PAH
OpenAlex ID: W4416770992