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Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting
Yao-Hua Song1, Yangxin Li, Jie Du
1Tulane University Health Sciences Center, New Orleans, Louisiana 70112-2699, USA.
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.
Insights
Angiotensin II infusion causes skeletal muscle wasting by reducing IGF-1 and activating muscle proteolysis. Restoring IGF-1 levels can block these effects, offering potential therapeutic strategies for muscle wasting conditions.
Area of Science:
- Biochemistry
- Physiology
- Molecular Biology
Background:
- Advanced congestive heart failure involves renin-angiotensin system activation and skeletal muscle wasting.
- Previous studies linked angiotensin II infusion to cachexia via increased muscle proteolysis and decreased IGF-1.
Purpose of the Study:
- To investigate the molecular mechanisms by which angiotensin II induces skeletal muscle wasting.
- To determine the role of Insulin-like Growth Factor-1 (IGF-1) in mediating or preventing angiotensin II-induced muscle atrophy.
Main Methods:
- Infusion of angiotensin II in rats and mice.
- Analysis of skeletal muscle signaling pathways, including Akt, caspase-3, and mTOR.
- Measurement of mRNA levels for ubiquitin ligases atrogin-1 and muscle ring finger-1.
- Utilizing muscle-specific IGF-1 expression models.
Main Results:
- Angiotensin II downregulated phospho-Akt and activated caspase-3 in skeletal muscle, leading to actin cleavage and apoptosis.
- Muscle-specific IGF-1 expression blocked these angiotensin II-induced changes.
- Angiotensin II upregulated atrogin-1 and muscle ring finger-1 mRNA levels in wild-type mice, but not in IGF-1-transgenic mice.
Conclusions:
- Angiotensin II-induced skeletal muscle wasting is causally linked to the downregulation of IGF-1 in skeletal muscle.
- The Akt/mTOR/p70S6K signaling pathway is implicated in IGF-1's protective effects.
- Findings suggest therapeutic potential for targeting the renin-angiotensin system and IGF-1 in catabolic conditions causing muscle wasting.
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