1. IGF- 1 prevents ANG Il-induced skeletal muscle atrophy via Akt- and Foxo-dependent inhibition of the ubiquitin ligase atrogin- 1 expression.
- Author
-
Yoshida, Tadashi, Semprun-Prieto, Laura, Sukhanov, Sergiy, and Delafontaine, Patrice
- Subjects
- *
MUSCULAR atrophy , *PHYSIOLOGICAL effects of angiotensins , *CONGESTIVE heart failure , *PROTEOLYSIS , *UBIQUITIN , *LIGASES , *APOPTOSIS - Abstract
Congestive heart failure is associated with activation of the reninangiotensin system and skeletal muscle wasting. Angiotensin II (ANG II) has been shown to increase muscle proteolysis and decrease circulating and skeletal muscle IGF-1. We have shown previously that skeletal muscle-specific overexpression of IGF-1 prevents proteolysis and apoptosis induced by ANG II. These findings indicated that downregulation of IGF-1 signaling in skeletal muscle played an important role in the wasting effect of ANG II. However, the signaling pathways and mechanisms whereby IGF-1 prevents ANG II-induced skeletal muscle atrophy are unknown. Here we show ANG II-induced transcriptional regulation of two ubiquitin ligases atroginI and muscle ring finger-I (MuRF-1) that precedes the reduction of skeletal muscle IGF-1 expression, suggesting that activation of atroginI and MuRF-1 is an initial mechanism leading to skeletal muscle atrophy in response to ANG II. IGF-1 overexpression in skeletal muscle prevented ANG II-induced skeletal muscle wasting and the expression of atroginI, but not MuRF-1. Dominant-negative Akt and constitutively active Foxo-1 blocked the ability of IGF-1 to prevent ANG IImediated upregulation of atrogin-1 and skeletal muscle wasting. Our findings demonstrate that the ability of IGF-1 to prevent ANG II-induced skeletal muscle wasting is mediated via an Aktand Foxo1-dependent signaling pathway that results in inhibition of atrogin-1 but not MuRFI expression. These data suggest strongly that atrogin-1 plays a critical role in mechanisms of ANG 11-induced wasting in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF