Nicotinic Acetylcholine Receptors Modulate T-Tubule Architecture Under Sympathetic Overstimulation

Pathological remodeling of transverse tubules (T-tubules, TTs) is commonly observed in cardiac disease and may be promoted by sustained adrenergic stimulation. Although cholinergic signaling has been associated with cardioprotective effects, it remains unclear whether it directly modulates TT integrity in cardiomyocytes. Here, we examined how cholinergic receptor activation affects TT organization during acute β-adrenergic stimulation in isolated adult rat cardiomyocytes. Cells were exposed to isoproterenol (ISO), alone or in combination with acetylcholine (ACh) or nicotine (Nic). Confocal imaging showed that ISO disrupted TT organization and reduced the cellular length-to-width (L/W) ratio. ACh or Nic alone altered TT architecture, primarily by reducing TT power and increasing longitudinal tubule density; however, co-treatment with either agonist was associated with altered TT remodeling responses to ISO in TT structure and cell morphology. The muscarinic receptor agonist xanomeline (Xano) did not reproduce these effects. These results suggest a cardiomyocyte-autonomous role for nAChR signaling in limiting acute β-adrenergic stimulation-induced TT remodeling. Further studies are required to identify the nAChR subtype and downstream signaling mechanisms involved and to determine the relevance of these findings in vivo.