Glucocorticoids induce bone and muscle atrophy by tissue-specific mechanisms upstream of E3 ubiquitin ligases

Amy Sato, Danielle Richardson, Meloney Cregor, Hannah M. Davis, Ernie D. Au, Kevin McAndrews, Teresa Zimmers, Jason Organ, Munro Peacock, Lilian Plotkin, Teresita Bellido

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Glucocorticoid excess, either endogenous with diseases of the adrenal gland, stress, or aging or when administered for immunosuppression, induces bone and muscle loss, leading to osteopenia and sarcopenia. Muscle weakness increases the propensity for falling, which, combined with the lower bone mass, increases the fracture risk. The mechanisms underlying glucocorticoid-induced bone and muscle atrophy are not completely understood. We have demonstrated that the loss of bone and muscle mass, decreased bone formation, and reduced muscle strength, hallmarks of glucocorticoid excess, are accompanied by upregulation in both tissues in vivo of the atrophy-related genes atrogin1, MuRF1, and MUSA1. These are E3 ubiquitin ligases traditionally considered muscle-specific. Glucocorticoids also upregulated atrophy genes in cultured osteoblastic/osteocytic cells, in ex vivo bone organ cultures, and in muscle organ cultures and C2C12 myoblasts/myotubes. Furthermore, glucocorticoidsmarkedly increased the expression of components of the Notch signaling pathway inmuscle in vivo, ex vivo, and in vitro. In contrast, glucocorticoids did not increase Notch signaling in bone or bone cells. Moreover, the increased expression of atrophy-related genes in muscle, but not in bone, and the decreasedmyotube diameter induced by glucocorticoids were prevented by inhibiting Notch signaling. Thus, glucocorticoids activate different mechanisms in bone and muscle that upregulate atrophy-related genes. However, the role of these genes in the effects of glucocorticoids in bone is unknown. Nevertheless, these findings advance our knowledge of the mechanism of action of glucocorticoids in the musculoskeletal system and provide the basis for novel therapies to prevent glucocorticoid-induced atrophy of bone and muscle.

Original languageEnglish (US)
Pages (from-to)664-677
Number of pages14
JournalEndocrinology
Volume158
Issue number3
DOIs
StatePublished - Mar 1 2017

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Ubiquitin-Protein Ligases
Muscular Atrophy
Glucocorticoids
Bone and Bones
Muscles
Atrophy
Genes
Organ Culture Techniques
Adrenal Gland Diseases
Up-Regulation
Sarcopenia
Musculoskeletal System
Metabolic Bone Diseases
Myoblasts
Skeletal Muscle Fibers
Muscle Weakness
Muscle Strength
Osteogenesis
Immunosuppression

ASJC Scopus subject areas

  • Endocrinology

Cite this

Glucocorticoids induce bone and muscle atrophy by tissue-specific mechanisms upstream of E3 ubiquitin ligases. / Sato, Amy; Richardson, Danielle; Cregor, Meloney; Davis, Hannah M.; Au, Ernie D.; McAndrews, Kevin; Zimmers, Teresa; Organ, Jason; Peacock, Munro; Plotkin, Lilian; Bellido, Teresita.

In: Endocrinology, Vol. 158, No. 3, 01.03.2017, p. 664-677.

Research output: Contribution to journalArticle

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