Muscle-specific expression of IGF-1 blocks angiotensin II–induced skeletal muscle wasting
Yao-Hua Song, Yangxin Li, Jie Du, William E. Mitch, Nadia Rosenthal, Patrick Delafontaine
Yao-Hua Song, Yangxin Li, Jie Du, William E. Mitch, Nadia Rosenthal, Patrick Delafontaine
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Article Cardiology

Muscle-specific expression of IGF-1 blocks angiotensin II–induced skeletal muscle wasting

Abstract

Advanced congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. We previously showed that angiotensin II infusion in rats produces cachexia secondarily to increased muscle proteolysis and also decreases levels of circulating and skeletal muscle IGF-1. Here we show that angiotensin II markedly downregulates phospho-Akt and activates caspase-3 in skeletal muscle, leading to actin cleavage, an important component of muscle proteolysis, and to increased apoptosis. These changes are blocked by muscle-specific expression of IGF-1, likely via the Akt/mTOR/p70S6K signaling pathway. We also demonstrate that mRNA levels of the ubiquitin ligases atrogin-1 and muscle ring finger–1 are upregulated in angiotensin II–infused WT, but not in IGF-1–transgenic, mice. These findings strongly suggest that angiotensin II downregulation of IGF-1 in skeletal muscle is causally related to angiotensin II–induced wasting. Because the renin-angiotensin system is activated in many catabolic conditions, our findings have broad implications for understanding mechanisms of skeletal muscle wasting and provide a rationale for new therapeutic approaches.

Authors

Yao-Hua Song, Yangxin Li, Jie Du, William E. Mitch, Nadia Rosenthal, Patrick Delafontaine

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Involvement of Akt/mTOR/p70S6K kinases in the ability of the MLC/mIgf-1 ...
Involvement of Akt/mTOR/p70S6K kinases in the ability of the MLC/mIgf-1 transgene to prevent angiotensin II–induced muscle loss. (A) Basal characterization of signaling pathways in MLC/mIgf-1 mice. Gastrocnemius lysates from WT or MLC/mIgf-1 mice were subjected to SDS-PAGE and Western blotting with indicated antibodies. There is no significant difference in baseline levels of IGF-1 receptor (IGF-1R), phospho- or total Akt, and phospho- or total MAPK in transgenics. (B) Phospho-mTOR and phospho-p70S6K expression was diminished in muscles of angiotensin II–infused WT mice compared with pair-fed controls but was maintained in the angiotensin II–infused MLC/mIgf-1 mice. Additionally, expression of phospho-mTOR and phospho-p70S6K was increased at basal levels in transgenic mice compared with WT. (C) Phospho-Akt expression was maintained in angiotensin II–infused MLC/mIgf-1 mice, accompanied by diminished caspase-3 cleavage. (D) The accumulation of 14-kDa actin fragment was significantly reduced in the angiotensin II–infused MLC/mIgf-1 mice compared with WT mice.