A preliminary assessment of physical function in aged male mice with constitutive activation of the aryl hydrocarbon receptors in skeletal muscle

Abstract

BACKGROUND: Aging involves a gradual deterioration of physical and physiological functions, ultimately leading to mortality. Unfortunately, there are no treatments available that successfully mitigate the age-associated decline in physical function. Recent studies have revealed a strong association between elevated levels of L-kynurenine (L-Kyn) and frailty, muscle weakness, and neuromuscular junction degeneration in humans and mice, however a causal relationship has not been tested. L-Kyn is a product of tryptophan catabolism that has been linked to motor neuron death, skeletal muscle atrophy, and mitochondrial dysfunction, all hallmarks of aging muscle. Interestingly, L-Kyn is an endogenous ligand of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor widely known for its role in xenobiotic metabolism. Though both pro- and anti-aging effects of the AHR have been reported in the literature, there are several chronic diseases that involve chronic AHR activation and produce strikingly similar phenotypes to exacerbated aging/frailty. OBJECTIVE: The objective of this study was to determine of constitutive activation of the AHR has a causal role in the decline of physical function with aging. METHODS: Aged (16-mo.) C57BL6 male mice (N=48) were obtained from the NIA breeding colony and were randomized to interventions employing muscle-specific adeno-associated virus with the following three treatment groups: 1) a constitutively active AHR mutant was constructed by deleting the ligand binding domain (amino acids 277-418); 2) a transcriptionally deficient AHR mutant (arginine to aspartate mutation at amino acid 39); and an empty vector control. Treadmill endurance, forelimb grip strength, and maximal walking speed were measured at 24-mos. of age. Results: Treadmill endurance capacity in mice with constitutively AHR activation was 5.3% lower than mice treated with the empty vector ( P=0.25) and 12.1% lower than mice treated with the transcriptionally deficient AHR mutant ( P=0.09). Grip strength and walking speed were not significantly different between groups ( P>0.57 and 0.22 respectively) at this 24-mo. age. CONCLUSIONS: These preliminary results in aging male C57BL6 mice may indicate possible role of AHR activation in the decline of physical function. Continued enrollment to increase the sample size and obtaining measures at later ages when physical function declines more severely, as well as examining female mice will provide a more thorough analysis. Funding Supported by grants from the National Institutes of Health R01-AG076490 (Ryan & Hepple) and T32 AG062728 (Wimberly). This is the full abstract presented at the American Physiology Summit 2024 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.