Muscleblind Splicing Factor Regulates Longevity Through p38 MAPK Signaling

Muscleblind-like splicing regulators (MBNLs) are alternative splicing 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 manifesting in symptoms resembling accelerated aging, we asked whether MBNLs are regulators of longevity. By utilizing the nematode C. elegans, we show that loss of MBL-1 (the sole ortholog of mammalian MBNLs) shortens lifespan by reducing the activity of conserved p38 MAPK signaling as well as the function of transcription factors ATF-7 and SKN-1. Furthermore, we found that modulation of p38 MAPK activity through mitochondrial stress results in significantly stronger lifespan extension in MBL-1-deficient C. elegans compared to wild-type. Together, the data presented here provide a previously unknown mechanism of how a DM1-associated alternative splicing factor regulates aging.

Keywords: Muscleblind-like splicing regulator, MBL-1, p38 MAPK signaling, mitochondrial stress, Aging, C. elegans

Suggested Citation: Suggested Citation

Matilainen, Olli and Ribeiro, Ana R. S. and Cetinbas, Murat and Sadreyev, Ruslan I. and Garcia, Susana M. D. A., Muscleblind Splicing Factor Regulates Longevity Through p38 MAPK Signaling. Available at SSRN: https://ssrn.com/abstract=3569543 or http://dx.doi.org/10.2139/ssrn.3569543

This version of the paper has not been formally peer reviewed.