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Cited by 12Genetics, Aging, and Longevity in Model OrganismsTryptophan and brain disordersMuscle Physiology and Disorders

Inhibition of AhR improves cortical bone and skeletal muscle function via preservation of neuromuscular junctions

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Yu, Kanglun, Vyavahare, Sagar, Alhamad, Dima, Bensreti, Husam, Ruan, Ling, Tuladhar, Anik, Dai, Caihong, Shaver, Joseph C. +13 more·2025·JCI Insight
DOI 10.1172/jci.insight.192047PMC PMC12406733
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Abstract

The aryl hydrocarbon receptor (AhR) is proposed to mediate the frailty-promoting effects of the tryptophan metabolite kynurenine, which increases with age in mice and humans. The goal of the current study was to test whether administration of pharmacological AhR inhibitors, BAY2416964 and CH-223191, could abrogate musculoskeletal decline in aging mice. Female C57BL/6 mice (18 months old) were treated with vehicle (VEH) or 30 mg/kg BAY2416964 (BAY) via daily oral gavage 5 days/week for 8 weeks. A second AhR antagonist, CH-223191, was administered to 16-month-old male and female C57BL/6 mice via intraperitoneal injections (3.3 mg/kg) 3 days/week for 12 weeks. While grip strength declined over time in VEH-treated mice, BAY preserved grip strength in part by improving integrity of neuromuscular junctions (NMJs), an effect replicated during in vitro studies with siRNA against AhR. Cortical bone mass was also greater in BAY- than VEH-treated mice. Similarly, CH-223191 treatment improved cortical bone and showed beneficial effects in skeletal muscle, including reducing oxidative stress as compared with VEH-treated animals. Transcriptomic and proteomic data from BAY-treated mice supported a positive impact of BAY on molecular targets that affect NMJ function. Taken together, these data support AhR as a therapeutic target for improving musculoskeletal health during aging.

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  • Pharmacologic AhR inhibition improves cortical bone quality in aging models.

    “Pharmacologic AhR inhibition has been shown to improve cortical bone quality in aging models, emphasizing its relevance to skeletal degeneration [58]”

    From Interorgan Communications in Skeletal Pathophysiology: From Molecular Pathways to Multidisciplinary Therapies (2026) · cites this paper as [58]

    The Discussion reports that pharmacologic AhR inhibition improved cortical bone mass in aged mice. The Results report greater cortical thickness and bone volume fraction with BAY treatment, but do not establish an improvement in cortical bone quality as distinct from those structural measures. (LLM, conf=0.82)

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Cited by

Sorted by citations

Authors
Yu, K., Vyavahare, S., Alhamad, D., Bensreti, H., Ruan, L., Tuladhar, A., Dai, C., Shaver, J. C., Tripathi, A., Ding, K., Pacholczyk, R., Cooley, M. A., Zhong, R., Johnson, M. H., Chen, J., Bollag, W. B., Isales, C. M., Hill, W. D., Hamrick, M. W., Fulzele, S., & McGee-Lawrence, M. E.
Affiliations
  • Augusta University (US)
  • Department of Medicine, Medical College of Georgia,
  • Georgia Cancer Center,
  • Department of Oral Biology & Diagnostic Sciences, Dental College of Georgia,
  • Medical University of South Carolina (US)
  • Department of Cellular Biology and Anatomy, Medical College of Georgia,
Corresponding author
Fulzele, Sadanand
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2025-07-15
Volume
10
Issue
16
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.192047
PMC
PMC12406733
OpenAlex
W4412430295
Cited by
12
References
5
Citations by year
2026: 9 · 2025: 3
FWCI
3.81
Type
journal article
Language
en
Open access
Licence
Locations
  • JCI Insight (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute on Aging (P01 AG036675, R01 067510)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR082307)
  • NIH Office of the Director (S10 OD025177)
  • Veterans Administration Medical Center (IK6 BX00569)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords
aryl hydrocarbon receptor, CH223191, kynurenine, tryptophan metabolism, aging, frailty, neuromuscular junction, cortical bone mass, skeletal muscle function, grip strength, oxidative stress, age-related decline
MeSH terms
Cortical Bone, Aging, Animals, Female, Humans, Male, Mice, Inbred C57BL, Neuromuscular Junction, Pyrazoles, Receptors, Aryl Hydrocarbon, Muscle, Skeletal, Hand Strength, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins

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