Calpain-dependent cleavage of junctophilin-2 and T-tubule remodeling in a mouse model of reversible heart failure

Chia-Yen C Wu; Biyi Chen; Ya-Ping Jiang; Zhiheng Jia; Dwight W Martin; Shengnan Liu; Emilia Entcheva; Long-Sheng Song; Richard Z Lin

doi:10.1161/JAHA.113.000527

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Calpain-dependent cleavage of junctophilin-2 and T-tubule remodeling in a mouse model of reversible heart failure

Journal article

Open access

Calpain-dependent cleavage of junctophilin-2 and T-tubule remodeling in a mouse model of reversible heart failure

Chia-Yen C Wu, Biyi Chen, Ya-Ping Jiang, Zhiheng Jia, Dwight W Martin, Shengnan Liu, Emilia Entcheva, Long-Sheng Song and Richard Z Lin

Journal of the American Heart Association, Vol.3(3), pp.e000527-n/a

06/23/2014

DOI: 10.1161/JAHA.113.000527

PMCID: PMC4309042

PMID: 24958777

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Abstract

A highly organized transverse tubule (T-tubule) network is necessary for efficient Ca(2+)-induced Ca(2+) release and synchronized contraction of ventricular myocytes. Increasing evidence suggests that T-tubule remodeling due to junctophilin-2 (JP-2) downregulation plays a critical role in the progression of heart failure. However, the mechanisms underlying JP-2 dysregulation remain incompletely understood. A mouse model of reversible heart failure that is driven by conditional activation of the heterotrimeric G protein Gαq in cardiac myocytes was used in this study. Mice with activated Gαq exhibited disruption of the T-tubule network and defects in Ca(2+) handling that culminated in heart failure compared with wild-type mice. Activation of Gαq/phospholipase Cβ signaling increased the activity of the Ca(2+)-dependent protease calpain, leading to the proteolytic cleavage of JP-2. A novel calpain cleavage fragment of JP-2 is detected only in hearts with constitutive Gαq signaling to phospholipase Cβ. Termination of the Gαq signal was followed by normalization of the JP-2 protein level, repair of the T-tubule network, improvements in Ca(2+) handling, and reversal of heart failure. Treatment of mice with a calpain inhibitor prevented Gαq-dependent JP-2 cleavage, T-tubule disruption, and the development of heart failure. Disruption of the T-tubule network in heart failure is a reversible process. Gαq-dependent activation of calpain and subsequent proteolysis of JP-2 appear to be the molecular mechanism that leads to T-tubule remodeling, Ca(2+) handling dysfunction, and progression to heart failure in this mouse model.

Animals

Calcium - metabolism

Calpain - physiology

Disease Notification

Down-Regulation - physiology

GTP-Binding Protein alpha Subunits, Gq-G11 - physiology

Heart Failure - physiopathology

Membrane Proteins - metabolism

Membrane Proteins - physiology

Mice

Mice, Inbred C57BL

Mice, Transgenic

Muscle Cells - physiology

Muscle Proteins - metabolism

Muscle Proteins - physiology

Proteolysis

Signal Transduction - physiology

Details

Title: Subtitle: Calpain-dependent cleavage of junctophilin-2 and T-tubule remodeling in a mouse model of reversible heart failure
Creators: Chia-Yen C Wu - Stony Brook University
Biyi Chen - University of Iowa
Ya-Ping Jiang - Stony Brook University
Zhiheng Jia - Stony Brook University
Dwight W Martin - Stony Brook University
Shengnan Liu - Stony Brook University
Emilia Entcheva - Stony Brook University
Long-Sheng Song - University of Iowa
Richard Z Lin - Stony Brook University
Resource Type: Journal article
Publication Details: Journal of the American Heart Association, Vol.3(3), pp.e000527-n/a
DOI: 10.1161/JAHA.113.000527
PMID: 24958777
PMCID: PMC4309042
NLM abbreviation: J Am Heart Assoc
ISSN: 2047-9980
eISSN: 2047-9980
Grant note: HL090905 / NHLBI NIH HHS R01 DK062722 / NIDDK NIH HHS R01 HL090905 / NHLBI NIH HHS CA136754 / NCI NIH HHS R01 CA136754 / NCI NIH HHS DK62722 / NIDDK NIH HHS
Language: English
Date published: 06/23/2014
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984288718902771

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