Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy, caused by an abnormal expansion of CTG repeats in the DMPK gene. It is a multisystemic disorder affecting skeletal muscle, the central nervous system, and the heart. Importantly, cardiac complications occur in over 80% of patients, including conduction defects and arrhythmias, and represent a major cause of morbidity and mortality. While the structural and electrophysiological consequences of DM1 in the heart have been described, the contribution of the autonomic nervous system remains poorly understood. We hypothesize that an imbalance of the autonomic nervous system, characterized by sympathetic hyperactivity, contributes to disease progression and cardiac dysfunction. To test this, we developed the first 3D human neuro-cardiac organoid model enabling precise control of sympathetic innervation. Ventricular cardiomyocyte organoids derived from human iPSCs were co-cultured with sympathetic neuron spheroids transduced with AAV-hSyn-ChR2(H134R)-EYFP, allowing optogenetic stimulation of neuronal terminals surrounding the organoids. Immunofluorescence confirmed close contacts between sympathetic fibers and cardiomyocytes, validating neuro-cardiac interfaces. Functional coupling was demonstrated by microelectrode arrays and optical mapping, showing robust cardiomyocyte responses upon neuronal activation. Applying this platform to DM1 patient-derived organoids, we observed hyperactive sympathetic firing and exaggerated cardiomyocyte responses upon stimulation. Compared to controls, DM1 organoids displayed altered conduction dynamics and increased excitability, consistent with disease-specific perturbations in sympathetic regulation. This integrated system, combining organoid engineering, immunofluorescence, optogenetics, and electrophysiology, provides a human-relevant model to dissect autonomic regulation of cardiac function. It enables mechanistic insights into neuro-cardiac signaling in both health and disease and establishes a framework for therapeutic screening targeting autonomic dysfunction. Our findings highlight the critical role of sympathetic innervation in cardiac regulation and demonstrate how this 3D neuro-cardiac platform can uncover pathophysiological mechanisms in DM1.
Jajkiewicz et al. (Sun,) studied this question.