RRC ID 76012
Author Matilainen O, Ribeiro ARS, Verbeeren J, Cetinbas M, Sood H, Sadreyev RI, Garcia SMDA.
Title Loss of muscleblind splicing factor shortens Caenorhabditis elegans lifespan by reducing the activity of p38 MAPK/PMK-1 and transcription factors ATF-7 and Nrf/SKN-1.
Journal Genetics
Abstract Muscleblind-like splicing regulators (MBNLs) are RNA-binding factors that have an important role in developmental processes. Dysfunction of these factors is a key contributor of different neuromuscular degenerative disorders, including Myotonic Dystrophy type 1 (DM1). Since DM1 is a multisystemic disease characterized by symptoms resembling accelerated aging, we asked which cellular processes do MBNLs regulate that make them necessary for normal lifespan. By utilizing the model organism Caenorhabditis elegans, we found that loss of MBL-1 (the sole ortholog of mammalian MBNLs), which is known to be required for normal lifespan, shortens lifespan by decreasing the activity of p38 MAPK/PMK-1 as well as the function of transcription factors ATF-7 and SKN-1. Furthermore, we show that mitochondrial stress caused by the knockdown of mitochondrial electron transport chain components promotes the longevity of mbl-1 mutants in a partially PMK-1-dependent manner. Together, the data establish a mechanism of how DM1-associated loss of muscleblind affects lifespan. Furthermore, this study suggests that mitochondrial stress could alleviate symptoms caused by the dysfunction of muscleblind splicing factor, creating a potential approach to investigate for therapy.
Volume 219(2)
Published 2021-10-2
DOI 10.1093/genetics/iyab114
PII 6325509
PMID 34849877
PMC PMC8633093
MeSH Activating Transcription Factors / metabolism* Animals Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* DNA-Binding Proteins / metabolism* Longevity / genetics* Mitogen-Activated Protein Kinases / metabolism* RNA-Binding Proteins / genetics RNA-Binding Proteins / metabolism* Transcription Factors / metabolism*
Resource
C.elegans tm1563