Evaluation of L-Kynurenine–Aryl Hydrocarbon Signaling as a Modulator of Physical Function in Aging Mice

BACKGROUND: Physical frailty is a significant contributor to poor health outcomes in the elderly, including increased mortality risk, emphasizing the need for effective interventions. Elevated levels of L-kynurenine (L-Kyn), a byproduct of tryptophan metabolism, have been linked to frailty, muscle weakness, and neuromuscular junction degeneration in both humans and rodents. L-Kyn is an endogenous ligand for the aryl hydrocarbon receptor (AHR), a transcription factor involved in xenobiotic metabolism whose persistent activation has been associated with various pathological conditions resembling those observed in frail older adults. OBJECTIVE. Using muscle-specific conditional AHR knockout mice, this study determined if inducible deletion of the AHR in old age could attenuate the effects of aging and elevating L-Kyn on skeletal muscle health/function and physical function. METHODS: Floxed AHR mice were bred with a tamoxifen-inducible skeletal muscle specific Cre line (Acta1-CreEsr1) to generate a skeletal muscle specific, inducible AHR knockout (AHRmKO). Mice of both sexes (N = 432; 230 Females (115 Cre+/- each); 202 Males (84 Cre+, 118 Cre-) were aged to 15 months. Baseline physical function assessments (forelimb grip strength, maximal walking speed, and treadmill endurance) were performed and then all mice received tamoxifen and were subsequently randomized to either chow or L-Kyn supplemented diets. A second tamoxifen delivery period was performed at 20 months of age to account for any incorporation of new nuclei to the muscle fibers. Physical function was re-assessed at 26 months of age followed by terminal experiments which included muscle mass, in situ neuromuscular contractile function, motor unit number estimation, and comprehensive mitochondrial phenotyping. RESULTS: Though there is an age dependent decline in physical function in both sexes, there was no significant variance in output when comparing different genotypes and feeding groups. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.