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- 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.
- Authors
Matilainen, Olli; Ribeiro, Ana R. S.; Verbeeren, Jens; Cetinbas, Murat; Sood, Heini; Sadreyev, Ruslan I.; Garcia, Susana M. D. A.
- 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.
- Subjects
RNA metabolism; GENETIC mutation; MUSCLES; CAENORHABDITIS elegans; ANIMAL experimentation; CELL membranes; CELL physiology; CELLULAR aging; MITOCHONDRIA; ELECTRON transport; MYOTONIA atrophica; TRANSCRIPTION factors; MITOGEN-activated protein kinases; LONGEVITY; CHEMICAL inhibitors
- Publication
Genetics, 2021, Vol 219, Issue 2, p1
- ISSN
0016-6731
- Publication type
Article
- DOI
10.1093/genetics/iyab114