Increased circulating levels of glucocorticoids observed in many catabolic conditions play a major role in the induction of muscle atrophy. Indeed, inhibition of glucocorticoid action by glucocorticoid receptor antagonist attenuates and, in some cases, abolishes muscle atrophy. Circulating and tissue levels of IGF-I, a growth factor that stimulates the development of muscle mass, are frequently reduced in response to glucocorticoids. This decline could therefore trigger muscle atrophy in catabolic conditions. Indeed, systemic administration of IGF-I prevents glucocorticoid-induced muscle atrophy. However, use of systemic IGF-I administration is limited by its hypoglycemic and cardiac hypertrophic actions. Moreover, local IGF-I seems to play a more important role in the regulation of muscle mass than systemic IGF-I. Therefore, to limit loss of muscle mass observed in catabolic states, IGF-I administration must mimic as close as possible the autocrine production of IGF-I.
The aim of this thesis was to investigate whether the restoration of IGF-I muscle content could reverse muscle atrophy induced by glucocorticoids. In this work we have tested the hypothesis that the local decrease in muscle IGF-I content might be responsible for the muscular atrophy induced by glucocorticoids.
In our work, we have demonstrated that localized overexpression of IGF-I by gene electrotransfer prevents muscle atrophy in glucocorticoid-treated rats. High rate of fiber transfection and long term gene expression were obtained by combining multiple injection sites of DNA with electroporation. Human IGF-I gene electrotransfer using this optimised protocol resulted in increased muscle IGF-I mRNA and protein levels together with prevention of loss of skeletal muscle mass. Furthermore, alterations in the Akt/GSK-3â/â-catenin signaling pathway caused by glucocorticoids were prevented by local IGF-I gene overexpression. Finally, muscle overexpression of caAkt, dnGSK-3b and ÄNb-catenin was sufficient to mimic the anti-atrophic effect of IGF-I supporting the role of this signalling pathway in muscle atrophy caused by glucocorticoids. Taken together, our results show, for the first time in vivo, the role of the IGF-I/Akt/GSK-3b/b-catenin pathway in the skeletal muscle atrophy caused by glucocorticoids. In conclusion, our work highlights the crucial role of decreased muscle IGF-I in glucocorticoid-induced muscle atrophy. Indeed, the data presented in this thesis support the fact that the atrophic action of glucocorticoids is in part due to the downregulation of IGF-I, leading to the inhibition of its signalling pathways while restoration of muscle IGF-I levels is able to counteract totally muscle atrophy.
| Identifer | oai:union.ndltd.org:BICfB/oai:ucl.ac.be:ETDUCL:BelnUcetd-02132009-124647 |
| Date | 10 February 2009 |
| Creators | Schakman, Olivier |
| Publisher | Universite catholique de Louvain |
| Source Sets | Bibliothèque interuniversitaire de la Communauté française de Belgique |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://edoc.bib.ucl.ac.be:81/ETD-db/collection/available/BelnUcetd-02132009-124647/ |
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