Transcriptional regulation of intermolecular Ca2+ signaling in hibernating ground squirrel cardiomyocytes: The myocardin-junctophilin axis

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

Research output: Contribution to journalArticlepeer-review

Abstract

The contraction of heart cells is controlled by the intermolecular signaling between L-type Ca2+ 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 Ca2+ 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.

Original languageEnglish (US)
Article numbere2025333118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number14
DOIs
StatePublished - Apr 6 2021
Externally publishedYes

Keywords

  • Calcium signal
  • Coupling
  • Excitation-contraction
  • Hibernation
  • Ion channel

ASJC Scopus subject areas

  • General

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