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Pharmacologic or genetic interference with atrogene signaling protects against glucocorticoid-induced musculoskeletal and cardiac disease
Amy Y. Sato, … , Tamara Alliston, Teresita Bellido
Amy Y. Sato, … , Tamara Alliston, Teresita Bellido
Published October 15, 2024
Citation Information: JCI Insight. 2024;9(21):e182664. https://doi.org/10.1172/jci.insight.182664.
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Research Article Bone biology Article has an altmetric score of 4

Pharmacologic or genetic interference with atrogene signaling protects against glucocorticoid-induced musculoskeletal and cardiac disease

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Abstract

Despite their beneficial actions as immunosuppressants, glucocorticoids (GC) have devastating effects on the musculoskeletal and cardiac systems, as long-term treated patients exhibit high incidence of falls, bone fractures, and cardiovascular events. Herein, we show that GC upregulate simultaneously in bone, skeletal muscle, and the heart the expression of E3 ubiquitin ligases (atrogenes), known to stimulate the proteasomal degradation of proteins. Activation of vitamin D receptor (VDR) signaling with the VDR ligands calcitriol or eldecalcitol prevented GC-induced atrogene upregulation in vivo and ex vivo in bone/muscle organ cultures and preserved tissue structure/mass and function of the 3 tissues in vivo. Direct pharmacologic inhibition of the proteasome with carfilzomib also conferred musculoskeletal protection. Genetic loss of the atrogene MuRF1-mediated protein ubiquitination in ΔRING mice afforded temporary or sustained protection from GC excess in bone or skeletal and heart muscle. We concluded that the atrogene pathway downstream of MuRF1 underlies GC action in bone, muscle, and the heart, and it can be pharmacologically or genetically targeted to confer protection against the damaging actions of GC simultaneously in the 3 tissues.

Authors

Amy Y. Sato, Meloney Cregor, Kevin McAndrews, Charles A. Schurman, Eric Schaible, Jennifer Shutter, Punit Vyas, Bhawana Adhikari, Monte S. Willis, Marjan Boerma, Tamara Alliston, Teresita Bellido

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Figure 5

Interference with the atrogene pathway confers musculoskeletal protection against excessive GC.

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Interference with the atrogene pathway confers musculoskeletal protectio...
Mice were implanted with 2.1 mg/kg/d prednisolone or placebo slow-release pellets and treated with 5 mg/kg/d carfilzomib or vehicle by intraperitoneal injection 2 times per week for 2 weeks. (A) BMD, (B) sera P1NP, (C) body weights, and (D) isolated skeletal muscle weights 2 weeks after the indicated treatments. n = 10–12. *P < 0.05 vs. corresponding placebos, #P < 0.05 vs. corresponding vehicle-treated, by 2-way ANOVA, Tukey’s post hoc test. (E) Skeletal muscle function, as assessed by plantarflexion torque in vivo testing measured after 2 weeks of the indicated treatments. n = 11–12. *P < 0.05 vs. corresponding placebos, #P < 0.05 vs. corresponding vehicle-treated. Main group effects are indicated by red symbols: red *P < 0.05 all corresponding placebos vs. all corresponding GC, by 2-way repeated-measures ANOVA, Tukey’s post hoc test.

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