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.
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