title: Glucocorticoids Induce Bone and Muscle Atrophy by Tissue-Specific Mechanisms Upstream of E3 Ubiquitin Ligases.
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, glucocorticoids markedly increased the expression of components of the Notch signaling pathway in muscle 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 decreased myotube 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.
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Sato
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Richardson
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Meloney
authors.initials: M
authors.lastname: Cregor
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Davis
authors.affiliation: Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.|Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Ernie D
authors.initials: ED
authors.lastname: Au
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana.
authors.forename: Kevin
authors.initials: K
authors.lastname: McAndrews
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.|Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana.|Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Zimmers
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biomedical Engineering, Indiana University-Purdue University, Indianapolis, Indiana.|Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Organ
authors.affiliation: Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.|Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA.
authors.forename: Munro
authors.initials: M
authors.lastname: Peacock
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana.|Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.
authors.forename: Lilian I
authors.initials: LI
authors.lastname: Plotkin
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA.|Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana.|Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000009:adverse effects*; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D009133:Muscular Atrophy / Q000139:chemically induced*; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D011897:Random Allocation; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D051880:Receptors, Notch; D044767:Ubiquitin-Protein Ligases