Studies on molecular mechanisms of recovery

A second focus remains the analysis of gene regulatory mechanisms in myocytes. This is based on in vitro cell culture techniques and has revealed that IGF-I is directly elevated in myocytes in response to the ß2-specifc agonist clenbuterol, and that this may act through an autocrine/paracrine mechanism to elicit a physiological myocyte hypertrophy. Together with Dr Nigel Brand we are dissecting both the mechanism of this response and its relationship to pathways of muscle atrophy involving ubiquitin ligases, atrogin-1/MAFbx1, Murf1 and the FOXO transcription factors. These pathways are known to be of central importance in skeletal muscle and are likely to regulate cardiac muscle atrophy in response to mechanical unloading. Understanding these pathways and their relationship to the effects of clenbuterol is therefore a key issue in understanding recovery in the Harefield recovery patients. The specific involvement of ubiquitin pathways are being investigated as a collaborative study with Dr Heinrich Taegtmeyer at the University of Texas Medical Science Centre Houston, USA.

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Further Reading

Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ (2004). The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell. 14 , 395-403.

Razeghi P, Sharma S, Ying J, Li YP, Stepkowski S, Reid MB, & Taegtmeyer H (2003). Atrophic remodeling of the heart in vivo simultaneously activates pathways of protein synthesis and degradation. Circulation 108 , 2536-2541.