Dexamethasone downregulates caveolin-1 causing muscle atrophy via inhibited insulin signaling
Young Hoon Son1, Seok-Jin Lee1, Ki-Baek Lee1
1Department 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.
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.
Insights
Glucocorticoids cause muscle atrophy by inhibiting insulin signaling. This study reveals glucocorticoids downregulate caveolin-1 (CAV1), a key protein, thus blocking insulin signaling and leading to muscle loss.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Glucocorticoids induce muscle atrophy in conditions like cancer and sepsis.
- Glucocorticoid-induced muscle atrophy is linked to the inhibition of insulin signaling pathways.
Purpose of the Study:
- To elucidate the novel mechanism by which glucocorticoids inhibit insulin signaling in muscle.
- To identify the role of caveolin-1 (CAV1) in glucocorticoid-induced muscle atrophy.
Main Methods:
- Utilized C2C12 myotubes and mouse models.
- Investigated the effects of dexamethasone (DEX) on CAV1, insulin receptor alpha (IRα), and insulin receptor substrate 1 (IRS1) expression.
- Employed gene knockdown (siRNA) and overexpression techniques for CAV1.
- Performed promoter analysis and site-directed mutagenesis on the Cav1 gene.
- Administered adenovirus expressing CAV1 into mouse gastrocnemius muscle.
Main Results:
- Dexamethasone treatment decreased CAV1, IRα, and IRS1 levels in myotubes.
- Identified a negative glucocorticoid-response element in the Cav1 gene promoter, confirming CAV1 as a glucocorticoid-target gene.
- CAV1 knockdown exacerbated the inhibition of insulin signaling, while CAV1 overexpression prevented DEX-induced decreases in IRα and IRS1.
- Overexpression of CAV1 in mouse muscle attenuated dexamethasone-induced muscle atrophy.
Conclusions:
- Caveolin-1 (CAV1) is a critical regulator of muscle homeostasis.
- CAV1 mediates the inhibition of insulin signaling by glucocorticoids.
- Targeting CAV1 offers a potential therapeutic strategy for preventing glucocorticoid-induced muscle atrophy.
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