Crosstalk between Vitamin D Receptor signaling and Glucocorticoids in Musculoskeletal induced Atrophy

Date of Award

5-5-2023

Document Type

Thesis

Department

Biology

First Reader

Dr. Tim Knight

Second Reader

Dr. Angela Douglass

Third Reader

Professor Jennifer Pittman

Abstract

Accumulation of glucocorticoids occurs through exposure to chemotherapy drug cocktails, immunosuppressants, stress, and aging, and leads to a loss of bone and muscle mass. Excess of glucocorticoids induces musculoskeletal atrophy and is now the third leading cause of osteoporosis. The goal of this project is to investigate whether increased vitamin D receptor (VDR) signaling interferes with glucocorticoid induced atrophy in bone and skeletal muscle, and to investigate the role of VDR signaling in skeletal muscle within this frame. Four-month-old mice that either expressed VDR in their skeletal muscles or had expression of VDR suppressed through genetic excision with Cre recombinase enzyme activity were used in this project. The mice were treated with either a placebo or glucocorticoids, and then the same mice were either dosed with the active metabolite vitamin D (1,25-dihydroxyvitamin D3) or a vehicle control. After 4 weeks of treatment, the lean body mass, gastrocnemius muscle weight, and bone mineral density of each mouse was collected. The lean body mass of the mice was decreased by glucocorticoids, and vitamin D intervention protected from this loss. The gastrocnemius muscle weight was decreased by glucocorticoids, and vitamin D prevented this loss only in mice that have skeletal muscle VDR expression, but not in mice that lack this expression. Glucocorticoids decreased bone mineral density, but vitamin D provided a partial protection from this loss. These findings indicate that vitamin D intervention might simultaneously protect against glucocorticoid induced musculoskeletal atrophy in immunosuppressant patients.

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