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J Biol Chem. 2013 Aug 16;288(33):23823-32. doi: 10.1074/jbc.M112.449074. Epub 2013 Jul 6.

Angiotensin II inhibits satellite cell proliferation and prevents skeletal muscle regeneration.

Author information

1
Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.

Abstract

Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Although patients with advanced CHF or CKD often have increased angiotensin II (Ang II) levels and cachexia and Ang II causes skeletal muscle wasting in rodents, the potential effects of Ang II on muscle regeneration are unknown. Muscle regeneration is highly dependent on the ability of a pool of muscle stem cells (satellite cells) to proliferate and to repair damaged myofibers or form new myofibers. Here we show that Ang II reduced skeletal muscle regeneration via inhibition of satellite cell (SC) proliferation. Ang II reduced the number of regenerating myofibers and decreased expression of SC proliferation/differentiation markers (MyoD, myogenin, and active-Notch) after cardiotoxin-induced muscle injury in vivo and in SCs cultured in vitro. Ang II depleted the basal pool of SCs, as detected in Myf5(nLacZ/+) mice and by FACS sorting, and this effect was inhibited by Ang II AT1 receptor (AT1R) blockade and in AT1aR-null mice. AT1R was highly expressed in SCs, and Notch activation abrogated the AT1R-mediated antiproliferative effect of Ang II in cultured SCs. In mice that developed CHF postmyocardial infarction, there was skeletal muscle wasting and reduced SC numbers that were inhibited by AT1R blockade. Ang II inhibition of skeletal muscle regeneration via AT1 receptor-dependent suppression of SC Notch and MyoD signaling and proliferation is likely to play an important role in mechanisms leading to cachexia in chronic disease states such as CHF and CKD.

KEYWORDS:

Angiotensin II; Cachexia; Myocardial Infarction; Regeneration; Satellite Cells; Skeletal Muscle; Stem Cells

PMID:
23831688
PMCID:
PMC3745329
DOI:
10.1074/jbc.M112.449074
[Indexed for MEDLINE]
Free PMC Article

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