Low TAS1R2 Sweet Taste Receptor Expression in Skeletal Muscle of Genetically Diverse BXD Mice Mirrors Transcriptomic Signatures of Loss-of-Function Mice.

Background/Objectives: Sweet taste receptor TAS1R2 is expressed in skeletal muscle, yet its role in muscle metabolism remains poorly understood. Methods: Here, we leverage the BXD recombinant inbred mouse panel and Tas1r2 whole-body knockout (bKO) models to investigate the transcriptional impact of Tas1r2 deficiency on skeletal muscle function. Results: A gene network analysis revealed significant overlap in transcriptomic signatures between BXD strains with low Tas1r2 expression (BXD LTas1r2) and bKO muscle, particularly in pathways regulating oxidative phosphorylation, cytoplasmic ribosome function, and proteostasis. Notably, Tas1r2 expression negatively correlated with genes involved in fatty acid metabolism, suggesting its role in lipid utilization. Under high-fat diet (HFD) conditions, BXDHFD LTas1r2 mice exhibited further enrichment in pathways linked to proteasome degradation, oxidative stress, and interleukin signaling, amplifying the transcriptomic convergence with bKO models. Key transcription factors (Mlxipl, Nfic, Rxrb) exhibited altered regulatory patterns under dietary stress, indicating that TAS1R2 influences metabolic adaptability through transcriptional reprogramming. Conclusions: Given that human TAS1R2 variants rarely result in complete loss of function (LOF), the BXD panel provides an effective dose-dependent model to bridge the gap between knockout phenotypes and human SNP carriers. Our findings establish TAS1R2 as a metabolic regulator in skeletal muscle and highlight the utility of genetically diverse mouse populations in dissecting gene-diet interactions relevant to human metabolic diseases.