Increasing autophagy and blocking Nrf2 suppress laminopathy-induced age-dependent cardiac dysfunction and shortened lifespan

Shruti Bhide; Adriana S Trujillo; Maureen T O'Connor; Grant H Young; Diane E Cryderman; Sahaana Chandran; Mastaneh Nikravesh; Lori L Wallrath; Girish C Melkani

doi:10.1111/acel.12747Aging

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Increasing autophagy and blocking Nrf2 suppress laminopathy-induced age-dependent cardiac dysfunction and shortened lifespan

Journal article

Open access

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Increasing autophagy and blocking Nrf2 suppress laminopathy-induced age-dependent cardiac dysfunction and shortened lifespan

Shruti Bhide, Adriana S Trujillo, Maureen T O'Connor, Grant H Young, Diane E Cryderman, Sahaana Chandran, Mastaneh Nikravesh, Lori L Wallrath and Girish C Melkani

Aging Cell, Vol.17(3), e12747

03/25/2018

DOI: 10.1111/acel.12747Aging

PMCID: PMC5946079

PMID: 29575479

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Published (Version of record)Aging Cell, 2018; 17: e12747.

Abstract

Mutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age-dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A-type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age-dependent heart defects are not well understood. To address this issue, we modeled human disease-causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over-expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies.

Biochemistry

Medical Biochemistry

autophagy

cardiac aging

Drosophila aging model

lamins

Nrf2/Keap1 pathway

protein aggregation

OAfund

myocardial disease

Details

Title: Subtitle: Increasing autophagy and blocking Nrf2 suppress laminopathy-induced age-dependent cardiac dysfunction and shortened lifespan
Creators: Shruti Bhide - San Diego State University
Adriana S Trujillo - San Diego State University
Maureen T O'Connor - University of Iowa
Grant H Young - University of Iowa
Diane E Cryderman - University of Iowa
Sahaana Chandran - San Diego State University
Mastaneh Nikravesh - San Diego State University
Lori L Wallrath - University of Iowa
Girish C Melkani - San Diego State University
Resource Type: Journal article
Publication Details: Aging Cell, Vol.17(3), e12747
Publisher: Wiley
DOI: 10.1111/acel.12747Aging
PMID: 29575479
PMCID: PMC5946079
ISSN: 1474-9726
Grant note: National Institute on Aging. Grant Number: AG049494

National Institutes of Health. Grant Number: AR064894

Muscular Dystrophy Association. Grant Number: 44728

Conflict of Interests: None declared.
Language: English
Date published: 03/25/2018
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9983557429602771

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