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
Copyright policy )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
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.
- Massachussetts General Hospital Harvard Medical School Neurogenetics Unit United States
- Harvard University United States
- University of Helsinki Finland
EXPRESSION, MITOCHONDRIAL DYSFUNCTION, STRESS, PROTEINS, Longevity, Muscleblind splicing factor, ATF-1, p38 MAPK, PMK-1, PATHWAY, SKN-1, KINASE, Animals, INNATE IMMUNE-RESPONSES, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Investigation, mitochondrial stress, RNA-Binding Proteins, MAPK, Activating Transcription Factors, DNA-Binding Proteins, Genetics, developmental biology, physiology, C. elegans, RNA, Mitogen-Activated Protein Kinases, FACTOR SKN-1, lifespan, Transcription Factors
EXPRESSION, MITOCHONDRIAL DYSFUNCTION, STRESS, PROTEINS, Longevity, Muscleblind splicing factor, ATF-1, p38 MAPK, PMK-1, PATHWAY, SKN-1, KINASE, Animals, INNATE IMMUNE-RESPONSES, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Investigation, mitochondrial stress, RNA-Binding Proteins, MAPK, Activating Transcription Factors, DNA-Binding Proteins, Genetics, developmental biology, physiology, C. elegans, RNA, Mitogen-Activated Protein Kinases, FACTOR SKN-1, lifespan, Transcription Factors
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