The Gut Microbiota and Metabolome and Brown Adipose Tissue Regulate the Enhanced Exercise Capacity in Mice with Disruption of the Regulator of G protein Signaling 14 (RGS14)

Abstract

The Gut Microbiota and Metabolome and Brown Adipose Tissue Regulate the Enhanced Exercise Capacity in Mice with Disruption of the Regulator of G protein Signaling 14 (RGS14) Candace R. Longoria, Olufunmilola Ibironke, Lee J. Kerkhof, Marko Oydanich, Xiaoyang Su, Eric Chiles, Dorothy E. Vatner, Stephen F. Vatner, Sara C. Campbell, FACSM.Rutgers, The State University of New Jersey Disruption of the Regulator of G Protein Signaling 14 (RGS14 (knockout) KO) results in a mouse model of healthful longevity with enhanced exercise capacity. Running distance and work to exhaustion are increased by 60±9% and 54±6% respectively in the RGS14 KO mouse compared to wild type littermates (WTL). Our hypothesis was that the enhanced exercise capacity was mediated by brown adipose tissue (BAT), which was confirmed by BAT transplants from RGS14 KO mice to WTL, resulting in a reversal of phenotype with the RGS14 KO mice losing the enhanced exercise capacity and WTL gaining the enhanced exercise capacity. We further hypothesized that the mechanism mediating the enhanced exercise capacity in RGS14 KO mice involved the gut microbiota and metabolome. The gut microbiota is linked to BAT, but the mechanisms and microbes facilitating BAT function remain largely unknown. Twenty-four mice were used to identify gut microbes by ribosomal operon profiling and metabolites in BAT samples at baseline. Bacterial differential expression analysis (via DESeq2) showed significant bacterial community differences between wild-type (WT) and RGS14 KO mice. Specifically, five bacterial strains ( Acutalibacter muris KB18, Ureaplasma urealyticum 132, Ureaplasma parvum ATCC 33697, Ureaplasma parvum, and Mucispirillum schaedleri ASF457) were present in RGS14 KO mice and not in WT. RGS14 KO mice also housed two distinctive strains of A. muciniphilia (BIOML-A22 and A. muciniphilia AN78). Eleven metabolites were significantly higher in RGS14 KO BAT samples compared to WT, with significant metabolic pathways, which in turn, are related to mechanisms mediating enhanced exercise capacity. We then examined the effects of antibiotic treatment (ABX) in 8 mice. Following 1 week of ABX, the bacterial strains that were increased in RGS14 KO mice were no longer elevated and the enhanced exercise capacity in RGS14 KO mice was no longer elevated compared to WTL. Furthermore, 6 of the 7 metabolites related to glucose and amino acid metabolism were no longer increased in RGS14 KO BAT compared to WTL. Taken together, these studies show that RGS14 KO BAT, associated with specific microbes and metabolites known to be involved with BAT, mediate the increased metabolic pathways that are associated with enhanced exercise capacity in RGS14 KO mice. In conclusion, the gut microbiota appears to be linked to RGS14 KO BAT function, which mediates enhanced exercise capacity in RGS14 KO mice. ONR Grant #826640 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.