Suppression of myopathic lamin mutations by muscle-specific activation of AMPK and modulation of downstream signaling

Sahaana Chandran; Jennifer A Suggs; Bingyan J Wang; Andrew Han; Shruti Bhide; Diane E Cryderman; Steven A Moore; Sanford I Bernstein; Lori L Wallrath; Girish C Melkani

doi:10.1093/hmg/ddy332

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Suppression of myopathic lamin mutations by muscle-specific activation of AMPK and modulation of downstream signaling

Journal article

Open access

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Suppression of myopathic lamin mutations by muscle-specific activation of AMPK and modulation of downstream signaling

Sahaana Chandran, Jennifer A Suggs, Bingyan J Wang, Andrew Han, Shruti Bhide, Diane E Cryderman, Steven A Moore, Sanford I Bernstein, Lori L Wallrath and Girish C Melkani

Human molecular genetics, Vol.28(3), pp.351-371

02/01/2019

DOI: 10.1093/hmg/ddy332

PMCID: PMC6337691

PMID: 30239736

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Abstract

Laminopathies are diseases caused by dominant mutations in the human LMNA gene encoding A-type lamins. Lamins are intermediate filaments that line the inner nuclear membrane, provide structural support for the nucleus and regulate gene expression. Drosophila melanogaster models of skeletal muscle laminopathies were developed to investigate the pathological defects caused by mutant lamins and identify potential therapeutic targets. Human disease-causing LMNA mutations were modeled in Drosophila Lamin C (LamC) and expressed in indirect flight muscle (IFM). IFM-specific expression of mutant, but not wild-type LamC, caused held-up wings indicative of myofibrillar defects. Analyses of the muscles revealed cytoplasmic aggregates of nuclear envelope (NE) proteins, nuclear and mitochondrial dysmorphology, myofibrillar disorganization and up-regulation of the autophagy cargo receptor p62. We hypothesized that the cytoplasmic aggregates of NE proteins trigger signaling pathways that alter cellular homeostasis, causing muscle dysfunction. In support of this hypothesis, transcriptomics data from human muscle biopsy tissue revealed misregulation of the AMP-activated protein kinase (AMPK)/4E-binding protein 1 (4E-BP1)/autophagy/proteostatic pathways. Ribosomal protein S6K (S6K) messenger RNA (mRNA) levels were increased and AMPKα and mRNAs encoding downstream targets were decreased in muscles expressing mutant LMNA relative controls. The Drosophila laminopathy models were used to determine if altering the levels of these factors modulated muscle pathology. Muscle-specific over-expression of AMPKα and down-stream targets 4E-BP, Forkhead box transcription factors O (Foxo) and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), as well as inhibition of S6K, suppressed the held-up wing phenotype, myofibrillar defects and LamC aggregation. These findings provide novel insights on mutant LMNA-based disease mechanisms and identify potential targets for drug therapy.

AMP-Activated Protein Kinases - metabolism

Nuclear Envelope - physiology

Humans

Lamins - physiology

Intracellular Signaling Peptides and Proteins - metabolism

Drosophila Proteins - metabolism

Drosophila melanogaster - genetics

Drosophila melanogaster - metabolism

Lamins - genetics

Drosophila Proteins - physiology

Cell Nucleus - metabolism

Models, Animal

Signal Transduction

Membrane Proteins - genetics

Lamin Type A - metabolism

Muscle, Skeletal - physiology

Peptide Initiation Factors - metabolism

AMP-Activated Protein Kinases - physiology

Nuclear Envelope - metabolism

Phenotype

Animals

Lamin Type A - genetics

Drosophila Proteins - genetics

Mutation

Intracellular Signaling Peptides and Proteins - physiology

Peptide Initiation Factors - physiology

Details

Title: Subtitle: Suppression of myopathic lamin mutations by muscle-specific activation of AMPK and modulation of downstream signaling
Creators: Sahaana Chandran - Department of Biology, Molecular Biology and Heart Institutes, San Diego State University, San Diego, CA, USA
Jennifer A Suggs - Department of Biology, Molecular Biology and Heart Institutes, San Diego State University, San Diego, CA, USA
Bingyan J Wang - Department of Biology, Molecular Biology and Heart Institutes, San Diego State University, San Diego, CA, USA
Andrew Han - Department of Biology, Molecular Biology and Heart Institutes, San Diego State University, San Diego, CA, USA
Shruti Bhide - Department of Biology, Molecular Biology and Heart Institutes, San Diego State University, San Diego, CA, USA
Diane E Cryderman - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Steven A Moore - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Sanford I Bernstein - Department of Biology, Molecular Biology and Heart Institutes, San Diego State University, San Diego, CA, USA
Lori L Wallrath - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Girish C Melkani - Department of Biology, Molecular Biology and Heart Institutes, San Diego State University, San Diego, CA, USA
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.28(3), pp.351-371
Publisher: England
DOI: 10.1093/hmg/ddy332
PMID: 30239736
PMCID: PMC6337691
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: R01 AR055958 / NIAMS NIH HHS R37 GM032443 / NIGMS NIH HHS U54 NS053672 / NINDS NIH HHS R01 GM032443 / NIGMS NIH HHS MR/L023784/1 / Medical Research Council
Language: English
Date published: 02/01/2019
Academic Unit: Pathology; Biochemistry and Molecular Biology; University College Courses
Record Identifier: 9984047726502771

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