Work

Dystrophin Loss in Engineered Heart Tissues Recapitulates Clinically Relevant Aspects of Dystrophic Cardiomyopathy

Year: 2025

Type: article

Abstract: Heart failure is the leading cause of death in patients with Duchenne muscular dystrophy (DMD), but the mechanisms underlying the associated dilated cardiomyopathy (DCM) are not fully understood. To address this gap, we generated engineered heart tissues (EHTs) using CRISPR-edited human induced pluripotent stem cell-derived cardiomyocytes that lack dystrophin. These dystrophic EHTs reproduced aspects of systolic and diastolic dysfunction seen in DMD-related DCM as they showed impaired contractile function and slower kinetics. Increased beat rate variability was also observed in dystrophic EHTs. Accompanying these facets of the DMD pathology were attenuated Ca2+ transients and delayed kinetics. Lastly, histological analysis of EHTs revealed that dystrophin-null cardiomyocytes had reduced size and shorter sarcomere lengths when compared to isogenic controls. Together, these findings demonstrate that EHTs provide a physiologically relevant human model of DMD-associated DCM and may serve as a valuable platform for mechanistic studies and therapeutic testing.

Source: Journal of Biomechanical Engineering

DOI: 10.1115/1.4070408

Authors: Alex J. Goldstein, Thomas P. Leahy, David L. Mack, Nathan J. Sniadecki

Institution: University of Washington

Language: English

Topic: Pluripotent Stem Cells Research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases