The Role of the Microbiome in the Improved Exercise Performance in the Regulator of G Protein Signaling 14 (rgs14) Knock Out (KO) Mice

The Regulator of G Protein Signaling 14 knockout (RGS14 KO) mouse strain has a unique brown adipose tissue (BAT) mechanism mediating its phenotype of healthful longevity and improved exercise performance. RGS14 KO mice demonstrated a 51 ± 8% increase in treadmill running distance before exhaustion and a 44 ± 7% increase in work to exhaustion compared to their wild type littermates (WTLs). Three days after BAT transplantation from RGS14 KO mice to WTL mice, the RGS14 KO BAT donor mice lost their enhanced exercise capacity, whereas it was gained in the WTL BAT recipients: their running distance and work to exhaustion rose by 46 ± 5% and 52 ± 7%, respectively. In contrast, when BAT was transplanted to WTL mice from other WTL mice, exercise capacity did not increase at 3 days after transplantation, but was only seen after 2 months post-transplantation. Based on these observations, our hypothesis was that the unique characteristics of RGS14 KO BAT, in inducing enhanced exercise capacity upon transplantation, are mediated by novel gene upregulation within the BAT, as well as potential interactions between the BAT and the microbiome. We found that RGS14 KO mice harbor two unique, health-beneficial strains of Akkermansia muciniphilia ( A. muciniphilia BIOML-A22 and A. muciniphilia AN78) in their gut and their BAT has a number of novel genes upregulated, including Lnpep (leucyl/cystinyl aminopeptidase), TFAM (transcription factor A, mitochondrial), and Lncbate10, the latter being a critical regulator of BAT differentiation. To address directly the role of the microbiome, the mice were treated with antibiotics for 1 week. Although WTL exercise capacity was not significantly different before and after antibiotic-induced microbiota clearance, the RGS14 KO mice lost their enhanced exercise capacity after antibiotic treatment: RGS14 KO running distance fell by 35 ± 7%, and work to exhaustion fell by 41 ± 7%. Thus, RGS14 KO BAT engages changes to resident commensal microbiota that are beneficial to exercise capacity and therefore represents a potential (and novel) therapeutic modality for improving exercise performance and for creating healthful longevity.