Rapamycin attenuates pathological hypertrophy caused by an absence of trabecular formation

Abstract

Cardiac trabeculae are mesh-like muscular structures within ventricular walls. Subtle perturbations in trabeculation are associated with many congenital heart diseases (CHDs), and complete failure to form trabeculae leads to embryonic lethality. Despite the severe consequence of an absence of trabecular formation, the exact function of trabeculae remains unclear. Since ErbB2 signaling plays a direct and essential role in trabecular initiation, in this study, we utilized the erbb2 zebrafish mutant as a model to address the function of trabeculae in the heart. Intriguingly, we found that the trabeculae-deficient erbb2 mutant develops a hypertrophic-like (HL) phenotype that can be suppressed by inhibition of Target of Rapamycin (TOR) signaling in a similar fashion to adult mammalian hearts subjected to mechanical overload. Further, cell transplantation experiments demonstrated that erbb2 mutant cells in an otherwise wildtype heart did not undergo hypertrophy, indicating that erbb2 mutant HL phenotypes are due to a loss of trabeculae. Together, we propose that trabeculae serve to enhance contractility and that defects in this process lead to wall-stress induced hypertrophic remodeling.

Zebrafish Heart Failure Models

“…Erb-B2 Receptor Tyrosine Kinase 2 (Erbb2) plays an important role in trabeculae formation ( Lee et al, 1995 ; Liu et al, 2010 ). Trabeculae-deficient erbb2 mutant embryonic zebrafish develop HCM-like phenotype for compensation of aberrant trabeculae formation ( Fleming et al, 2018 ). Rapamycin treatment rescues impaired cardiac contractility and cardiac hypertrophy through the inhibition of target of rapamycin (TOR) pathway.…”

Understanding the Role of ztor in Aging-related Diseases Using the Zebrafish Model

“…ztor involvement in zebrafish development and growth is well described. These include the requirement for ztor activation for gut epithelial morphogenesis (46), axon regeneration (47), synaptic reinforcement and formation of new connections for learning and memory (48,49), angiogenesis (50) and cardiac trabeculation (51). Conversely, over-activation of ztor can lead to an early onset of epilepticlike phenotypic features in zebrafish (52).…”