title: Dexamethasone downregulates caveolin-1 causing muscle atrophy via inhibited insulin signaling.
abstract: Glucocorticoids play a major role in the development of muscle atrophy in various medical conditions, such as cancer, burn injury, and sepsis, by inhibiting insulin signaling. In this study, we report a new pathway in which glucocorticoids reduce the levels of upstream insulin signaling components by downregulating the transcription of the gene encoding caveolin-1 (CAV1), a scaffolding protein present in the caveolar membrane. Treatment with the glucocorticoid dexamethasone (DEX) decreased CAV1 protein and Cav1 mRNA expression, with a concomitant reduction in insulin receptor alpha (IRα) and IR substrate 1 (IRS1) levels in C2C12 myotubes. On the basis of the results of promoter analysis using deletion mutants and site-directed mutagenesis a negative glucocorticoid-response element in the regulatory region of the Cav1 gene was identified, confirming that Cav1 is a glucocorticoid-target gene. Cav1 knockdown using siRNA decreased the protein levels of IRα and IRS1, and overexpression of Cav1 prevented the DEX-induced decrease in IRα and IRS1 proteins, demonstrating a causal role of Cav1 in the inhibition of insulin signaling. Moreover, injection of adenovirus expressing Cav1 into the gastrocnemius muscle of mice prevented DEX-induced atrophy. These results indicate that CAV1 is a critical regulator of muscle homeostasis, linking glucocorticoid signaling to the insulin signaling pathway, thereby providing a novel target for the prevention of glucocorticoid-induced muscle atrophy.
authors: Department of Biochemistry and Molecular BiologyInstitute of Human-Environment Interface BiologyDepartment of Rehabilitation MedicineSeoul National University College of Medicine, 103 Daehak-ro, Jongno-Gu, Seoul 110-799, Korea.
authors: Young Hoon
authors: YH
authors: Son
authors: Department of Biochemistry and Molecular BiologyInstitute of Human-Environment Interface BiologyDepartment of Rehabilitation MedicineSeoul National University College of Medicine, 103 Daehak-ro, Jongno-Gu, Seoul 110-799, Korea.
authors: Seok-Jin
authors: SJ
authors: Lee
authors: Department of Biochemistry and Molecular BiologyInstitute of Human-Environment Interface BiologyDepartment of Rehabilitation MedicineSeoul National University College of Medicine, 103 Daehak-ro, Jongno-Gu, Seoul 110-799, Korea.
authors: Ki-Baek
authors: KB
authors: Lee
authors: Department of Biochemistry and Molecular BiologyInstitute of Human-Environment Interface BiologyDepartment of Rehabilitation MedicineSeoul National University College of Medicine, 103 Daehak-ro, Jongno-Gu, Seoul 110-799, Korea.
authors: Jin-Haeng
authors: JH
authors: Lee
authors: Department of Biochemistry and Molecular BiologyInstitute of Human-Environment Interface BiologyDepartment of Rehabilitation MedicineSeoul National University College of Medicine, 103 Daehak-ro, Jongno-Gu, Seoul 110-799, Korea Department of Biochemistry and Molecular BiologyInstitute of Human-Environment Interface BiologyDepartment of Rehabilitation MedicineSeoul National University College of Medicine, 103 Daehak-ro, Jongno-Gu, Seoul 110-799, Korea.
authors: Eui Man
authors: EM
authors: Jeong
authors: Department of Biochemistry and Molecular BiologyInstitute of Human-Environment Interface BiologyDepartment of Rehabilitation MedicineSeoul National University College of Medicine, 103 Daehak-ro, Jongno-Gu, Seoul 110-799, Korea.
authors: Sun Gun
authors: SG
authors: Chung
authors: Department of Biochemistry and Molecular BiologyInstitute of Human-Environment Interface BiologyDepartment of Rehabilitation MedicineSeoul National University College of Medicine, 103 Daehak-ro, Jongno-Gu, Seoul 110-799, Korea.
authors: Sang-Chul
authors: SC
authors: Park
authors: Department of Biochemistry and Molecular BiologyInstitute of Human-Environment Interface BiologyDepartment of Rehabilitation MedicineSeoul National University College of Medicine, 103 Daehak-ro, Jongno-Gu, Seoul 110-799, Korea Department of Biochemistry and Molecular BiologyInstitute of Human-Environment Interface BiologyDepartment of Rehabilitation MedicineSeoul National University College of Medicine, 103 Daehak-ro, Jongno-Gu, Seoul 110-799, Korea igkim@plaza.snu.ac.kr.
authors: In-Gyu
authors: IG
authors: Kim
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000494:pharmacology*; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000378:metabolism; D020033:Protein Isoforms; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D051242:Caveolin 1; D007328:Insulin; D020033:Protein Isoforms; D003907:Dexamethasone
keywords: C2C12 myotube; caveolin-1; glucocorticoid; insulin signaling; muscle atrophy