Abstract
There is more skeletal muscle tissue in the body than any other tissue and, as it is the organ of the majority of metabolic activity, muscle defect can affect the health of the entire body. Endoplasmic reticulum (ER) stress due to defects in protein folding/degradation balance, altered calcium and lipid levels and alterations in ER-mitochondria contacts has recently been recognised as the pathogenic cause of many different myopathies. In addition, a maladaptive ER stress response triggered by ER stress and mediated by three ER stress sensors (PERK, IRE1 and ATF6) is involved in a failure to relieve muscle tissue from this stress. Targeting ER stress and the ER stress response pathway offers a broad range of opportunities for treating myopathies but, as the inhibition of the three ER stress sensors may not be safe because it could lead to unexpected effects; it therefore calls for careful analysis of the changes in downstream signal transduction in the different myopathies so these sub-pathways can be pharmacologically targeted. This review summarises the known inhibitors of the ER stress response and the successful results obtained using some of them in mouse models of muscle diseases caused by ER stress/ER stress response.
Copyright © 2019 The Author. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Activating Transcription Factor 6 / antagonists & inhibitors
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Activating Transcription Factor 6 / genetics
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Activating Transcription Factor 6 / metabolism
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Aldehydes / pharmacology
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Animals
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Endoplasmic Reticulum / drug effects*
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Endoplasmic Reticulum / metabolism
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Endoplasmic Reticulum / pathology
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Endoplasmic Reticulum Stress / drug effects
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Endoribonucleases / antagonists & inhibitors
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Endoribonucleases / genetics
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Endoribonucleases / metabolism
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Gene Expression Regulation / drug effects*
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Humans
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Indoles / pharmacology
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Mice
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitochondria / pathology
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Molecular Targeted Therapy / methods
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / metabolism
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Muscle Fibers, Skeletal / pathology
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Muscle, Skeletal / drug effects*
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology
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Muscular Diseases / drug therapy*
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Muscular Diseases / genetics
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Muscular Diseases / metabolism
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Muscular Diseases / pathology
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Phenylbutyrates / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction
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Sulfonamides / pharmacology*
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Thiophenes / pharmacology*
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eIF-2 Kinase / antagonists & inhibitors
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eIF-2 Kinase / genetics
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eIF-2 Kinase / metabolism
Substances
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7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine
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ATF6 protein, human
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Activating Transcription Factor 6
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Aldehydes
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Indoles
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Phenylbutyrates
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STF 083010
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Sulfonamides
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Thiophenes
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salicylaldehyde
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4-phenylbutyric acid
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EIF2AK3 protein, human
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ERN1 protein, human
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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Endoribonucleases
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Adenine