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 7

CH-223191 treatment is beneficial for cortical bone and skeletal muscle.

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CH-223191 treatment is beneficial for cortical bone and skeletal muscle....
(A–E) Cortical bone mass, as measured by microCT; cortical bone volume fraction (A), cortical bone tissue volume (C), and cortical bone thickness (D) were not affected by CH-223191 treatment, while cortical bone volume (B) was significantly greater in CH-223191– as compared with VEH-treated mice, and similar trends are shown for polar moment of inertia (E). Trabecular bone (F–I) was largely unaffected by CH-223191 except for a demonstration of increased trabecular number in male but not female CH-223191–treated mice (I). While quadriceps mass was not affected by CH-223191 (J), average muscle fiber size in the TA muscle was increased in male CH-223191–treated mice (K), and metrics of oxidative stress (from Amplex Red assays) were reduced by CH-223191 in skeletal muscle from both sexes (L). P values from 2-way ANOVA with Fisher’s LSD post hoc analysis comparing groups are shown on each graph; group with different superscript letters are significantly (P < 0.05) different from one another as shown by post hoc testing.