Axial stretch-dependent cation entry in dystrophic cardiomyopathy: Involvement of several TRPs channels

Abstract

In Duchenne muscular dystrophy (DMD), deficiency of the cytoskeletal protein dystrophin leads to well-described defects in skeletal muscle but also to dilated cardiomyopathy (DCM). In cardiac cells, the subsarcolemmal localization of dystrophin is thought to protect the membrane from mechanical stress. The dystrophin deficiency leads to membrane instability and a high stress-induced Ca2+ influx due to dysregulation of sarcolemmal channels such as stretch-activated channels (SACs). In this work divalent cation entry has been explored in isolated ventricular Wild Type (WT) and mdx cardiomyocytes in two different conditions: at rest and during the application of an axial stretch. At rest, our results suggest that activation of TRPV2 channels participates to a constitutive basal cation entry in mdx cardiomyocytes.Using microcarbon fibres technique, an axial stretchwas applied to mimic effects of physiological conditions of ventricular filling and study on cation influx bythe Mn2+-quenching techniquedemonstrated a high stretch-dependentcationic influx in dystrophic cells, partially due to SACs. Involvement of TRPs channels in this excessive Ca2+ influx has been investigated using specific modulators and demonstratedboth sarcolemmal localization and an abnormal activity of TRPV2 channels. In conclusion, TRPV2 channels are demonstrated here to play a key role in cation influx and dysregulation in dystrophin deficient cardiomyocytes, enhanced in stretching conditions.

Quantitative tests reveal that microtubules tune the healthy heart but underlie arrhythmias in pathology

“…; Aguettaz et al . ). A stretch‐activated Ca 2+ influx (SACa) current was added to the existing computational model and was constrained by Ca 2+ influx measurements shown here (see Fig.…”

“…Evidence suggests that sarcolemmal stretch-activated channels (SACs; i.e. TRPs) contribute to the dynamic regulation of Ca 2+ in cardiomyocytes (Zeng et al 2000;Kondratev et al 2005;Aguettaz et al 2016). A stretch-activated Ca 2+ influx (SACa) current was added to the existing computational model and was constrained by Ca 2+ influx measurements shown here (see Fig.…”

Fine Tuning of Calcium Constitutive Entry by Optogenetically-Controlled Membrane Polarization: Impact on Cell Migration

“…The cytosolic calcium concentration under basal conditions achieves a steady-state equilibrium whereby calcium influx through constitutively active channels is balanced by efflux across the plasma membrane. Such constitutive calcium entry (CCE) through TRP channels has been widely related to the homeostatic function in normal cells as well as dysfunction in pathological conditions [2][3][4][5]. This form of calcium influx is due to the fact that some types of channels can be open at rest, with the amplitude of the influx strongly dependent on the membrane potential and associated calcium driving force.…”

“…This form of calcium influx is due to the fact that some types of channels can be open at rest, with the amplitude of the influx strongly dependent on the membrane potential and associated calcium driving force. Whereas TRP and CCE have been identified in several cell types [3][4][5], the resting membrane potential of these cells can vary widely depending on the excitable or non-excitable nature of the cell type under investigation. Excitable cells, such as neurons or cardiac and skeletal muscle cells, are characterized by their polarized resting membrane potentials in the −50 mV to −90 mV range and their ability to generate action potentials.…”

Mitochondrial mechanosensor in cardiovascular diseases

“…The heart modulates its function via a plethora of physiological and metabolic processes, necessary to supply oxygen, biochemical and biomolecular signals, and metabolites to the entire body ( 1 ). One of those physiological processes is the mechano-transduction that, via several actors like stretch-activated channels (SACS ( 2 )), the sarcoplasmic reticulum (SR) ( 3 ), ryanodine receptor (RyR ( 4 )), structural proteins ( 5 ) oxidative species ( 6 ), hormones ( 7 , 8 ), and ion channels ( 9 ), modulate calcium signaling in the myocytes and the pumping function of the heart.…”