Transcriptional Regulation of Intermolecular Ca Signaling in Hibernating Ground Squirrel Cardiomyocytes: The Myocardin-junctophilin Axis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2021 Mar 31

PMID 33785600

Citations 7

Authors

Lei Yang

Rong-Chang Li

Bin Xiang

Yi-Chen Li

Li-Peng Wang

Yun-Bo Guo

Jing-Hui Liang

Xiao-Ting Wang

Tingting Hou

Xin Xing

Zeng-Quan Zhou

Haihong Ye

Ren-Qing Feng

Edward G Lakatta

Zhen Chai

Shi-Qiang Wang

Affiliations

Soon will be listed here.

Abstract

The contraction of heart cells is controlled by the intermolecular signaling between L-type Ca channels (LCCs) and ryanodine receptors (RyRs), and the nanodistance between them depends on the interaction between junctophilin-2 (JPH2) in the sarcoplasmic reticulum (SR) and caveolin-3 (CAV3) in the transversal tubule (TT). In heart failure, decreased expression of JPH2 compromises LCC-RyR communication leading to deficient blood-pumping power. In the present study, we found that JPH2 and CAV3 transcription was concurrently regulated by serum response factor (SRF) and myocardin. In cardiomyocytes from torpid ground squirrels, compared with those from euthermic counterparts, myocardin expression was up-regulated, which boosted both JPH2 and CAV3 expression. Transmission electron microscopic imaging showed that the physical coupling between TTs and SRs was tightened during hibernation and after myocardin overexpression. Confocal Ca imaging under the whole-cell patch clamp condition revealed that these changes enhanced the efficiency of LCC-RyR intermolecular signaling and fully compensated the adaptive down-regulation of LCCs, maintaining the power of heart contraction while avoiding the risk of calcium overload during hibernation. Our finding not only revealed an essential molecular mechanism underlying the survival of hibernating mammals, but also demonstrated a "reverse model of heart failure" at the molecular level, suggesting a strategy for treating heart diseases.

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