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Testosterone protects against dexamethasone-induced muscle atrophy, protein degradation and MAFbx upregulation
Weidong Zhao1, Jiangping Pan, Zingbo Zhao
1Department of Veterans Affairs, Room 1E-02, James J. Peters VA Medical Center, Bronx, NY 10468, USA.
Abstract:
Administration of glucocorticoids in pharmacological amounts results in muscle atrophy due, in part, to accelerated degradation of muscle proteins by the ubiquitin-proteasome pathway. The ubiquitin ligase MAFbx is upregulated during muscle loss including that caused by glucocorticoids and has been implicated in accelerated muscle protein catabolism during such loss. Testosterone has been found to reverse glucocorticoid-induced muscle loss due to prolonged glucocorticoid administration. Here, we tested the possibility that testosterone would block muscle loss, upregulation of MAFbx, and protein catabolism when begun at the time of glucocorticoid administration. Coadministration of testosterone to male rats blocked dexamethasone-induced reduction in gastrocnemius muscle mass and upregulation of MAFbx mRNA levels. Administration of testosterone together with dexamethasone also prevented glucocorticoid-induced upregulation of MAFbx mRNA levels and protein catabolism in C2C12 myotube expressing the androgen receptor. Half-life of MAFbx was not altered by testosterone, dexamethasone or the combination. Testosterone blocked dexamethasone-induced increases in activity of the human MAFbx promotor. The findings indicate that administration testosterone prevents glucocorticoid-induced muscle atrophy and suggest that this results, in part at least, from reductions in muscle protein catabolism and expression of MAFbx.
Insights
Testosterone administration prevents glucocorticoid-induced muscle atrophy by reducing muscle protein breakdown and the expression of MAFbx (muscle atrophy F-box). This finding offers a potential therapeutic strategy for mitigating steroid-induced muscle wasting.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Pharmacological glucocorticoids accelerate muscle protein degradation via the ubiquitin-proteasome pathway.
- Muscle atrophy, induced by glucocorticoids, involves the upregulation of the ubiquitin ligase MAFbx (muscle atrophy F-box).
- Testosterone has previously shown efficacy in reversing established glucocorticoid-induced muscle loss.
Purpose of the Study:
- To investigate whether testosterone administration, initiated concurrently with glucocorticoids, can prevent muscle atrophy.
- To determine if testosterone blocks the upregulation of MAFbx and subsequent protein catabolism induced by glucocorticoids.
- To elucidate the mechanism by which testosterone may counteract glucocorticoid effects on muscle.
Main Methods:
- Coadministration of testosterone and dexamethasone to male rats to assess effects on gastrocnemius muscle mass and MAFbx mRNA levels.
- In vitro studies using C2C12 myotubes expressing the androgen receptor to evaluate MAFbx mRNA levels and protein catabolism.
- Analysis of MAFbx mRNA and protein half-life, and assessment of testosterone's effect on MAFbx promoter activity.
Main Results:
- Testosterone coadministration prevented dexamethasone-induced reductions in gastrocnemius muscle mass and MAFbx mRNA upregulation in rats.
- Testosterone inhibited dexamethasone-induced MAFbx mRNA upregulation and protein catabolism in androgen receptor-expressing C2C12 myotubes.
- Testosterone blocked the increase in human MAFbx promoter activity caused by dexamethasone, without altering MAFbx half-life.
Conclusions:
- Testosterone administration effectively prevents glucocorticoid-induced muscle atrophy when given concurrently.
- Testosterone's protective effect is partly mediated by reducing muscle protein catabolism and suppressing MAFbx expression.
- These findings suggest testosterone as a potential therapeutic agent to mitigate muscle loss associated with glucocorticoid therapy.
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