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. 2005 Feb;115(2):451-8.
doi: 10.1172/JCI22324.

Muscle-specific Expression of IGF-1 Blocks Angiotensin II-induced Skeletal Muscle Wasting

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Free PMC article

Muscle-specific Expression of IGF-1 Blocks Angiotensin II-induced Skeletal Muscle Wasting

Yao-Hua Song et al. J Clin Invest. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Angiotensin II produces muscle wasting in mice. C57BL/6 mice were either angiotensin II infused or sham infused and pair fed. Angiotensin II (A) markedly increased blood pressure (*P < 0.001, angiotensin II–infused vs. pair-fed), (B) produced relative weight loss (**P < 0.01 angiotensin II–infused vs. pair-fed), and (C and D) reduced muscle mass (***P < 0.05, angiotensin II–infused vs. pair-fed). A, angiotensin II–infused; P, pair-fed.
Figure 2
Figure 2
Angiotensin II decreases Akt phosphorylation and activates caspase-3, producing actin cleavage and increased protein ubiquitinization in skeletal muscle. Mice were either angiotensin II infused or sham infused and pair fed (n = 5 per group, 7 days) and gastrocnemius lysates assessed for (A) caspase-3 activity (*P < 0.01 angiotensin II– vs. sham-infused); (B) levels of activated (17-kDa) caspase-3 by Western blotting; (C) actin cleavage as determined by accumulation of 14-kDa actin fragment; (D) accumulation of 14-kDa actin fragment with or without caspase-3 inhibitor DEVD-CHO; (E) expression of proteins conjugated to ubiquitin (Ub); (F) expression levels of phospho–Akt (p-Akt), total Akt (t-Akt), phospho- and total Foxos, and phospho-GSK3β and total GSK3β; and (G) Ser307 phosphorylation of IRS-1 after immunoprecipitation with anti–IRS-1 antibody and SDS-PAGE and Western blotting. A/DE and P/DE, angiotensin II–infused and pair-fed with caspase-3 inhibitor DEVD-CHO, which was added to muscle lysates; A/DC and P/DC, angiotensin II–infused and pair-fed with caspase inhibitor Z-Asp-2,6-dichlorobenzoyloxymethylketone, which was administered to mice for 7 days.
Figure 3
Figure 3
Angiotensin II–induced muscle wasting in mice is in part glucocorticoid dependent. Mice were either angiotensin II infused or sham infused with daily injections of RU486 or vehicle and pair fed. RU486 significantly inhibited the angiotensin II–induced (A) relative loss of body weight (P < 0.01, angiotensin II–infused with RU486 [RA] vs. angiotensin II–infused), and (B and C) decrease in muscle mass as assessed at 7 days. RP, pair-fed with RU486.
Figure 4
Figure 4
Skeletal muscle–specific expression of an IGF-1 transgene blocks angiotensin II–induced wasting. WT or transgenic (Tg) mice were either angiotensin II infused or sham infused and pair fed for 7 days, and daily weights were measured (A and B) and muscle weights obtained at 7 days (CE). The relative weight loss in angiotensin II–infused WT mice (A; *P < 0.01 WT/angiotensin II–infused vs. WT/pair-fed) was blocked in transgenic mice (B) with preferential fast-fiber effect (C and D).
Figure 5
Figure 5
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.
Figure 6
Figure 6
Angiotensin II–induced muscle loss in WT mice is associated with (A) reduced levels of phospho-Bad in gastrocnemius muscle; (B) increased cytochrome c release into the cytosolic fraction (*P < 0.05, angiotensin II–infused vs. pair-fed WT); and (C) DNA fragmentation as detected by cell death ELISA (**P < 0.01, angiotensin II–infused vs. pair-fed WT). These changes were completely blunted in the transgenic mice (AC).

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