Inhibition of AhR improves cortical bone and skeletal muscle function via preservation of neuromuscular junctions
Kanglun Yu, Sagar Vyavahare, Dima Alhamad, Husam Bensreti, Ling Ruan, Anik Tuladhar, Caihong Dai, Joseph C. Shaver, Alok Tripathi, Kehong Ding, Rafal Pacholczyk, Marion A. Cooley, Roger Zhong, Maribeth H. Johnson, Jie Chen, Wendy B. Bollag, Carlos M. Isales, William D. Hill, Mark W. Hamrick, Sadanand Fulzele, Meghan E. McGee-Lawrence
Kanglun Yu, Sagar Vyavahare, Dima Alhamad, Husam Bensreti, Ling Ruan, Anik Tuladhar, Caihong Dai, Joseph C. Shaver, Alok Tripathi, Kehong Ding, Rafal Pacholczyk, Marion A. Cooley, Roger Zhong, Maribeth H. Johnson, Jie Chen, Wendy B. Bollag, Carlos M. Isales, William D. Hill, Mark W. Hamrick, Sadanand Fulzele, Meghan E. McGee-Lawrence
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Research Article Aging Bone biology

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

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.

Authors

Kanglun Yu, Sagar Vyavahare, Dima Alhamad, Husam Bensreti, Ling Ruan, Anik Tuladhar, Caihong Dai, Joseph C. Shaver, Alok Tripathi, Kehong Ding, Rafal Pacholczyk, Marion A. Cooley, Roger Zhong, Maribeth H. Johnson, Jie Chen, Wendy B. Bollag, Carlos M. Isales, William D. Hill, Mark W. Hamrick, Sadanand Fulzele, Meghan E. McGee-Lawrence

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Figure 6

BMSCs from BAY-treated mice showed enhanced colony formation and produce more matrix in vitro.

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BMSCs from BAY-treated mice showed enhanced colony formation and produce...
Crystal violet staining of BMSC-derived colonies on (A) day 7 and (B) day 14 in culture show increased colony formation by cells isolated from BAY-treated mice as shown by quantification of crystal violet–stained area normalized to total well area. (C) Alizarin red staining (normalized to total well area) was also enhanced in BMSC-derived osteoblast cultures isolated from BAY- as compared with VEH-treated mice. Each well shown represents 1 technical replicate culture. (D) Gene expression analyses from BMSC-derived osteoblast cultures on day 21 in culture. P values from Student’s t tests comparing groups are shown above each graph.