The antiretroviral drug emtricitabine increases kynurenine: tryptophan ratio, aryl hydrocarbon receptor activation, and cellular senescence in female mice

HIV-associated mortality has been reduced by antiretroviral therapies (ART), but prolonged ART usage by people living with HIV (PLWH) is associated with frailty and poor healthspan. Mechanisms driving this phenomenon are not fully known, but clinical and preclinical studies suggest that HIV and ART may drive aberrant activation of the aryl hydrocarbon receptor (AhR) by kynurenine (KYN), an endogenous metabolite of tryptophan. Therefore, we investigated whether the combination of an HIV-like phenotype (Tg26 mice) and treatment with ART (emtricitabine; FTC) in female mice alters skeletal muscle homeostasis in an AhR-dependent manner to promote premature muscle aging phenotypes. Short-term FTC treatment increased serum KYN:tryptophan ratio and activated AhR signaling in skeletal muscle of Tg26 mice, although the study duration was not sufficient to induce significant FTC-related functional decline. FTC, alone or in combination with other ART (tenofovir alafenamide and tenofovir disproxil fumarate), activated AhR and induced senescence of female myoblasts in a manner comparable to KYN. Sequencing-based studies revealed targets and pathways related to the impacts of an HIV phenotype and ART in female skeletal muscle, including Gnas (encoding Gsα protein, critical for muscle glucose metabolism), inflammatory pathways, and lipid metabolism. Our studies suggest that the combined presence of HIV viral proteins and exposure to ART induced activation of AhR-mediated signaling in female muscle, as well as widespread changes across the skeletal muscle transcriptome and methylation landscape that may contribute to development of muscle dysfunction. This suggests AhR may represent a novel target for addressing persistent disparities in healthspan for PLWH.