OR29-04 Vitamin D Signaling Prevents Glucocorticoid-Induced Musculoskeletal Tissue Loss And Cardiac Dysfunction By Targeting The Atrogene Pathway
Authors: Sato Amy , Cregor Meloney , Adhikari Bhawana , Boerma Marjan , Bellido Teresita 
Published: October 2023

Abstract
Disclosure: A. Sato: None. M. Cregor: None. B. Adhikari: None. M. Boerma: None. T. Bellido: None.
Glucocorticoid excess increases the risk of bone fractures and induces cardiovascular events. Earlier studies demonstrated that glucocorticoids upregulate the expression of E3 ubiquitin ligases (atrogenes) in bone and skeletal/cardiac muscles, suggesting a common targetable pathway to prevent harmful glucocorticoid actions. Atrogenes stimulate proteasomal degradation of proteins, which promotes musculoskeletal tissue loss and cardiac dysfunction, known hallmarks of glucocorticoid disease. Here, we investigated whether Vitamin D receptor activation, which has beneficial musculoskeletal effects and may prevent falls, blocks glucocorticoid-induced activation of the atrogene pathway. Skeletally mature female 4-month-old C57Bl6 mice (N=12) were implanted with placebo or 2.1mg/kg/d prednisolone pellets for 8wks and received vehicle or 50ng/kg/d of 1,25D3 (calcitriol), 5x/wk, starting 3d before pellet implantation. In bone, 1,25D3 fully prevented decreases in spinal bone mineral density (BMD) and cancellous bone microarchitectural deterioration (low BV/TV and Tb.Th) induced by glucocorticoids. 1,25D3 prevented glucocorticoid-induced resorption, as quantified by circulating CTX and osteoclast number/surface. In contrast, 1,25D3 did not prevent glucocorticoid-induced suppression of bone formation, as quantified by circulating markers (P1NP and osteocalcin) and histomorphometric indexes (MS/BS and BFR). In skeletal muscle, 1,25D3 fully prevented glucocorticoid-induced loss of lean body mass, a muscle mass index measured by DEXA, and decreases in muscle strength, as determined by in vivo plantarflexion torque testing of the posterior hindlimb muscular compartment. Consistent with clinical evidence, cardiac echocardiography detected glucocorticoid dysfunction as exhibited by left ventricular (LV) wall thinning (anterior and posterior LVs at diastole and systole) and inefficient heart contraction (increased LV systolic volume, reduced ejection fraction and fractional shortening). Remarkably, 1,25D3 prevented the cardiac LV thinning and dysfunction induced by glucocorticoids. Neither glucocorticoid nor 1,25D3 altered heart mass, LV mass, or heart rate. 1,25D3 also prevented glucocorticoid increases in atrogene MuRF1 expression in cardiac and skeletal tissues. Additionally, 1,25D3 prevented glucocorticoid-induced increases in atrogene expression in separate ex vivo organ cultures of bone, skeletal muscle, and left ventricles of the heart, demonstrating direct Vitamin D actions. In conclusion, 1) atrogene upregulation is a central mechanistic hub underlying the damaging actions of glucocorticoid excess in bone, skeletal muscle, and the heart and 2) activation of Vitamin D receptor signaling preserves tissue structure and function by interfering with the atrogene pathway in musculoskeletal and cardiac systems.
Presentation: Sunday, June 18, 2023