Morphogenesis of T-tubules in heart cells: the role of junctophilin-2

The T-tubule (TT) system forms the structural basis for excitation-contraction coupling in heart and muscle cells. The morphogenesis of the TT system is a key step in the maturation of heart cells because it does not exist in neonatal cardiomyocytes. In the present study, we quantified the morphological changes in TTs during heart cell maturation and investigated the role of junctophilin-2 (JP2), a protein known to anchor the sarcoplasmic reticulum (SR) to TT, in changes to TT morphological parameters. Analysis of confocal images showed that the transverse elements of TTs increased, while longitudinal elements decreased during the maturation of TTs. Fourier transform analysis showed that the power of ~2 m spatial components increased with cardiomyocytes maturation. These changes were preceded by increased expression of JP2, and were reversed by JP2 knockdown. These findings indicate that JP2 is required for the morphogenesis of TTs during heart development.

Mechanisms underlying the impaired contractility of diabetic cardiomyopathy

Cardiac dysfunction is a well-known consequence of diabetes,with sustained hyperglycaemia leading to the development of a cardiomyopathy that is independent of cardiovascular disease or hypertension.Animal models of diabetes are commonly used to study the pathophysiology of diabetic cardiomyopathy,with the hope that increased knowledge will lead ultimately to better therapeutic strategies being developed.At physiological temperature,left ventricular trabeculae isolated from the streptozotocin rat model of type 1 diabetes showed decreased stress and prolonged relaxation,but with no evidence that decreased contractility was a result of altered myocardial Ca2+handling.Although sarcoplasmic reticulum(SR)Ca2+reuptake appeared slower in diabetic trabeculae,it was offset by an increase in actionpotential duration,thereby maintaining SR Ca2+content and favouring increased contraction force.Frequency analysis of t-tubule distribution by confocal imaging of ventricular tissue labeled with wheat germ agglutinin or ryanodine receptor antibodies showed a reduced T-power for diabetic tissue,but the differences were minor in comparison to other models of heart failure.The contractile dysfunction appeared to be the result of disrupted F-actin in conjunction with the increased typeⅠcollagen,with decreased myofilament Ca2+sensitivity contributing to the slowed relaxation.

Cardiac BIN1(cBIN1) is a regulator of cardiac contractile function and an emerging biomarker of heart muscle health

In recent decades,a cardiomyocyte membrane scaffolding protein bridging integrator 1(BIN1) has emerged as a critical multifunctional regulator of transverse-tubule(t-tubule) function and calcium signaling in cardiomyocytes.Encoded by a single gene with 20 exons that are alternatively spliced,more than ten BIN1 protein isoforms are expressed with tissue and disease specificity.The recently discovered cardiac alternatively spliced isoform BIN1(cBIN1 or BIN1 +13 + 17)plays a crucial role in organizing membrane microfolds within cardiac t-tubules.These cBIN1-induced microfolds form functional dyad microdomains by trafficking L-type calcium channels(LTCC) to t-tubule membrane and recruiting ryanodine receptors(RyR) to junctional sarcoplasmic reticulum membrane.When cBIN1 is transcriptionally reduced as occurs in heart failure,cBIN1-microfolds are disrupted and fail to form LTCC and RyR couplons.As a result,impaired dyad formation limits excitation-contraction coupling thus cardiac contractility,and accumulation of orphaned leaky RyRs outside of dyads increases ventricular arrhythmias.Reduced myocardial BIN1 in heart failure is also detectable at the blood level,and plasma BIN1 level predicts heart failure progression and future arrhythmias in cardiomyopathy patients.Here we will review the recent progress in BIN1-related cardiomyocyte biology studies and discuss the diagnostic and predictive values of cBIN1 in future clinical use.