Sanchez Cabo, F. | bioRxiv Science

bioRxiv2025

AXL governs axolotl cardiac regeneration and directs mammalian cardiomyocyte dedifferentiation

Cardiac injury outcomes vary widely across species, from complete regeneration to irreversible scarring. Using single-nucleus multiomics and spatial transcriptomics, we generated a spatially resolved atlas of axolotl heart regeneration following injury, identifying a distinct border-zone cardiomyocyte population with a pro-regenerative transcriptional program. Ligand-receptor analysis of the border zone niche identified enrichment of the receptor tyrosine kinase AXL in injury-responsive cardiomyocytes and its ligand Gas6 in endothelial cells. Functional perturbation demonstrated AXL requirement for border-zone cardiomyocyte activation and axolotl heart regeneration. In murine cardiomyocytes, AXL overexpression induced sarcomere disassembly, metabolic rewiring, and immature gene expression without triggering proliferation. These findings show that AXL signaling induces cardiomyocyte dedifferentiation and uncouples dedifferentiation from cell cycle re-entry, providing mechanistic insight into cellular plasticity during heart regeneration.

cell biology↗

bioRxiv2024

Broad therapeutic benefit of myosin inhibition in hypertrophic cardiomyopathy

Myosin inhibitor mavacamten is the only targeted treatment available for hypertrophic cardiomyopathy (HCM), a disease caused by hundreds of genetic variants that affect mainly sarcomeric myosin and its negative regulator cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3). Here, we have examined whether the reported limited efficacy of mavacamten in a fraction of HCM patients can result from dissimilar HCM pathomechanisms triggered by different genetic variants, a scenario particularly relevant for MYBPC3-associated HCM. To this aim, we have generated knock-in mice including missense pathogenic variant cMyBP-C p.R502W, which, different from patients who carry truncations in the protein, develop progressive pathogenic myocardial remodeling in the absence of alterations of cMyBP-C levels and localization. Mechanistically, we find that mutation R502W reduces the binding affinity of cMyBP-C for myosin without inducing a shift towards more active myosin conformations as observed when cMyBP-C levels are reduced. Despite these diverging molecular alterations, we show that mavacamten blunts myocardial remodeling both in R502W and cMyBP-C-deficient, knock-out hearts. These beneficial effects are accompanied by improved tolerance to exercise only in R502W animals. Hence, our results indicate that myosin inhibition is effective to treat HCM caused by both truncating and missense variants in MYBPC3 regardless of the primary pathomechanisms they elicit.

physiology↗