한빛사논문
- 조회649
Evan E Santo 1, Rasmus Ribel-Madsen 2 3, Peter J Stroeken 4, Vincent C J de Boer 5, Ninna S Hansen 6, Maaike Commandeur 4, Allan A Vaag 6 7, Rogier Versteeg 4, Jihye Paik 1, Ellen M Westerhout 4
1Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA.
2The Novo Nordisk Foundation Center for Basic Metabolic Research, Clinical Pharmacology, Copenhagen, Denmark.
3The Danish Diabetes Academy, Odense, Denmark.
4Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
5Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands.
6Department of Biomedical Sciences, Endocrinology and Metabolism, University of Copenhagen, Copenhagen, Denmark.
7Department of Clinical Sciences, Clinical Research Centre, Lund University, Malmö, Sweden.
CORRESPONDING AUTHORS: Evan E. Santo, Jihye Paik
Abstract
Intronic single-nucleotide polymorphisms (SNPs) in FOXO3A are associated with human longevity. Currently, it is unclear how these SNPs alter FOXO3A functionality and human physiology, thereby influencing lifespan. Here, we identify a primate-specific FOXO3A transcriptional isoform, FOXO3A-Short (FOXO3A-S), encoding a major longevity-associated SNP, rs9400239 (C or T), within its 5' untranslated region. The FOXO3A-S mRNA is highly expressed in the skeletal muscle and has very limited expression in other tissues. We find that the rs9400239 variant influences the stability and functionality of the primarily nuclear protein(s) encoded by the FOXO3A-S mRNA. Assessment of the relationship between the FOXO3A-S polymorphism and peripheral glucose clearance during insulin infusion (Rd clamp) in a cohort of Danish twins revealed that longevity T-allele carriers have markedly faster peripheral glucose clearance rates than normal lifespan C-allele carriers. In vitro experiments in human myotube cultures utilizing overexpression of each allele showed that the C-allele represses glycolysis independently of PI3K signaling, while overexpression of the T-allele represses glycolysis only in a PI3K-inactive background. Supporting this finding inducible knockdown of the FOXO3A-S C-allele in cultured myotubes increases the glycolytic rate. We conclude that the rs9400239 polymorphism acts as a molecular switch which changes the identity of the FOXO3A-S-derived protein(s), which in turn alters the relationship between FOXO3A-S and insulin/PI3K signaling and glycolytic flux in the skeletal muscle. This critical difference endows carriers of the FOXO3A-S T-allele with consistently higher insulin-stimulated peripheral glucose clearance rates, which may contribute to their longer and healthier lifespans.
논문정보
- Research article
- 2023년 01월 (BRIC 등록일 2023-01-25)
- 국외 연구진
- 의약학 > 분자세포의학
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