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Review
. 2010 May;13(3):225-9.
doi: 10.1097/mco.0b013e32833862df.

Signaling pathways perturbing muscle mass

David J Glass  1
Affiliations
Review

Signaling pathways perturbing muscle mass

David J Glass. Curr Opin Clin Nutr Metab Care. 2010 May.

Abstract

Purpose of review: To discuss the mechanisms of muscle loss during cachexia.

Recent findings: Cachexia can be defined as a wasting of lean body mass that cannot be reversed nutrionally, indicating a dysregulation in the pathways maintaining body composition. In skeletal muscle, during cachexia, there is an upregulation of protein degradation. A search for transcriptional markers of muscle atrophy led to the discovery of the E3 ubiquitin ligases MuRF1 and MAFbx (also called Atrogin-1). These genes are upregulated in multiple models of atrophy and cachexia. They target particular protein substrates for degradation via the ubiquitin/proteasome pathway. The insulin-like growth factor-1 can block the transcriptional upregulation of MuRF1 and MAFbx via the phosphatidylinositol-3 kinase/Akt/Foxo pathway. MuRF1's substrates include several components of the sarcomeric thick filament, including myosin heavy chain. Thus, by blocking MuRF1, insulin-like growth factor-1 prevents the breakdown of the thick filament, particularly myosin heavy chain, which is asymmetrically lost in settings of cortisol-linked skeletal muscle atrophy. Insulin-like growth factor-1/phosphatidylinositol-3 kinase/Akt signaling also dominantly inhibits the effects of myostatin, which is a member of the transforming growth factor-[beta] family of proteins. Deletion or inhibition of myostatin causes a significant increase in skeletal muscle size. Recently, myostatin has been shown to act both by inhibiting gene activation associated with differentiation, even when applied to postdifferentiated myotubes, and by blocking the phosphatidylinositol-3 kinase/Akt pathway.

Summary: These findings will help to define strategies to treat cachexia.

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