Duchenne muscular dystrophy (DMD) is a rare X-linked disease caused by mutations in DMD, which encodes the membrane protein dystrophin. Although the earliest clinical presentation affects skeletal muscle, dystrophin loss in cardiac muscle is a significant source of morbidity and mortality for patients with DMD in their second decade of life and beyond. Despite progress in the treatment of the skeletal muscle pathology, development of effective therapies for the dystrophic cardiomyopathy is lagging, primarily due to sub-optimal models and complications in clinical trial design.
In vitro cardiomyocyte models from patient-derived induced pluripotent stem cells (iPSCs) are a promising technology for studying the mechanisms of dystrophic cardiomyopathy and the development of novel treatments. However, these models are typically cultured in conditions that do not mimic the mechanical stresses cardiomyocytes undergo in situ.
To address this issue, Dominic Fullenkamp and colleagues engineered and optimised a culture system that exposed human iPSC-derived cardiomyocytes (hiPSC-CMs) from a patient with DMD with severe cardiomyopathy to radial deformation, and used proteomics to assess the response to this mechanical stress.
Previous studies on animal models and sera from patients with DMD showed that dystrophin deficiency renders cardiomyocytes more prone to injury upon mechanical stress. This was indeed recapitulated in the hiPSC-CM model, as demonstrated by the elevated release of clinically relevant mechanical stress biomarkers from the dystrophin-deficient cells upon deformation-induced injury. To assess the utility of this model in testing therapeutic interventions, the authors treated the DMD hiPSC-CM model with recombinant annexin A6, a known membrane repair protein. This treatment reduced the release of injury biomarkers, confirming the validity of their model for testing membrane-resealing therapies to mitigate cellular injury.
Taken together, these results confirm the importance of mechanical stress in DMD-related cardiac pathology. Importantly, they underscore how incorporating mechanical stress into in vitro cardiac models of DMD is essential for model validity. When optimised to encompass as many aspects of the pathology as possible, in vitro models are a promising technology for meaningful translational advances for rare diseases that affect the heart.
The image shows flexed cardiomyocyte release biomarkers such as those seen in patients with muscular dystrophy. For permission to reuse, please contact Dominic Fullenkamp (firstname.lastname@example.org).
DMM Research or Resource & Methods articles of particular interest or excellence may be accompanied by a short Editor's choice highlight, selected by a DMM editor and written by either members of the DMM in-house editorial team or an expert in the field. The Editor's choice aims to outline the challenges that the work addresses and how the work advances our insight into disease mechanism, therapy or diagnosis.