Post-transcriptional regulation of energy usage: glucose and lipid metabolism

National Institute On Aging

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Abstract

The studies in this Project focus on understanding the RNA-binding proteins (RBPs) and noncoding (nc)RNAs that influence energy metabolism, since the processes that generate energy become impaired with aging. Historically, we have studied the regulation of insulin production, adipogenesis, and myogenesis by RBPs and ncRNAs. GLUCOSE HOMEOSTASIS. With rising appreciation that glucose metabolism is extensively regulated at the post-transcriptional level, we continue efforts to identify regulators pancreatic cell function and glucose homeostasis. A mouse model is being generated that overexpresses HuD in neuronal and pancreatic beta cells, and another in which HuD is knocked out in the same two tissues. MITOCHONDRIA. Over the past reporting period, we have made important progress towards understanding the role and metabolism of long noncoding (lnc)RNA in mitochondrial function. Some mitochondrial lncRNAs are encoded by nuclear DNA, but the mechanisms that mediate their transport to mitochondria are poorly characterized. One such nuclear DNA-encoded lncRNA, RMRP, was found to be the target of RBPs HuR and GRSF1, which associated with RMRP and mobilized it to mitochondria. In cultured human cells, HuR bound RMRP in the nucleus and exported it to the cytosol; subsequently, GRSF1 facilitated the function of RMRP in the mitochondria. Accordingly, silencing GRSF1 impaired the import of RMRP into mitochondria and lowered oxygen consumption rates. We discovered a mechanism whereby RBPs mediate the transport of nuclear DNA-encoded lncRNAs into the mitochondria (Noh et al., Genes and Development, 2016) and identified the roles of the mitochondrial RBP GRSF1 in the response to stresses causing cell sensecence (Noh et al., Nucleic Acids Res 2019). In this review period, we reported that GRSF1 deficiency in skeletal muscle reduced exercise endurance in aged mice (Driscoll et al., Aging 2021). MYOGENESIS. During this review period, we reported that the circular RNA circSamd4 promoted mouse myogenesis by transcriptionally inactivating PUR proteins (Pandey et al., Nucleic Acids Research, 2020) and that the long noncoding OIP5-AS1 associated with MEF2C mRNA to enhanced human myogenesis (Yang et al., Nucleic Acids Research, 2020). In collaboration with Dr. Ferrucci (Translational Gerontology Branch) we performed ribosome analysis of aging human skeletal muscle (Tharakan et al., RNA Biology 2021) and we cataloged the skeletal muscle transcriptome in healthy aging (Tumasian et al., Nature Communications, 2021).