Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I

Endocrinology. 2001 Apr;142(4):1489-96. doi: 10.1210/endo.142.4.8082.

Abstract

We previously showed that angiotensin II (ang II) infusion in the rat produces cachexia and decreases circulating insulin-like growth factor I (IGF-I). The weight loss derives from an anorexigenic response and a catabolic effect of ang II. In these experiments we assessed potential catabolic mechanisms and the involvement of the IGF-I system in these responses to ang II. Ang II infusion caused a significant decrease in body weight compared with that of pair-fed control rats. Kidney and left ventricular weights were significantly increased by ang II, whereas fat tissue was unchanged. Skeletal muscle mass was significantly decreased in the ang II-infused rats, and a reduction in lean muscle mass was a major reason for their overall loss of body weight. In skeletal muscles, ang II did not significantly decrease protein synthesis, but overall protein breakdown was accelerated; inhibiting lysosomal and calcium-activated proteases did not reduce the ang II-induced increase in muscle proteolysis. Circulating IGF-I levels were 33% lower in ang II rats vs. control rats, and this difference was reflected in lower IGF-I messenger RNA levels in the liver. Moreover, IGF-I, IGF-binding protein-3, and IGF-binding protein-5 messenger RNAs in the gastrocnemius were significantly reduced. To investigate whether the reduced circulating IGF-I accounts for the loss in muscle mass, we increased circulating IGF-I by coinfusing ang II and IGF-I, but this did not prevent muscle loss. Our data suggest that ang II causes a loss in skeletal muscle mass by enhancing protein degradation probably via its inhibitory effect on the autocrine IGF-I system.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Autocrine Communication / drug effects*
  • Blotting, Northern
  • Blotting, Western
  • Body Weight / drug effects
  • Down-Regulation / drug effects*
  • Insulin-Like Growth Factor I / biosynthesis*
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / pharmacology
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Muscle Proteins / biosynthesis
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Nuclease Protection Assays
  • Organ Size / drug effects
  • RNA, Messenger / biosynthesis
  • Radioimmunoassay
  • Rats
  • Rats, Sprague-Dawley
  • Wasting Syndrome / chemically induced*
  • Wasting Syndrome / pathology

Substances

  • Muscle Proteins
  • RNA, Messenger
  • Angiotensin II
  • Insulin-Like Growth Factor I