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

We previously showed that angiotensin II (ang II) infusion in the rat produ ces cachexia and decreases circulating insulin-like growth factor I (IGF-I) . The weight loss derives from an anorexigenic response and a catabolic eff ect of ang II. In these experiments we assessed potential catabolic mechani sms and the involvement of the IGF-I system in these responses to ang II. A ng II infusion caused a significant decrease in body weight compared with t hat of pair-fed control rats. Kidney and left ventricular weights were sign ificantly increased by ang II, whereas fat tissue was unchanged. Skeletal m uscle mass was significantly decreased in the ang II-infused rats, and a re duction in lean muscle mass was a major reason for their overall loss of bo dy weight. In skeletal muscles, ang II did not significantly decrease prote in synthesis, but overall protein breakdown was accelerated; inhibiting lys osomal and calcium-activated proteases did not reduce the ang II-induced in crease in muscle proteolysis. Circulating IGF-I levels were 33% lower in an g II rats us. 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 signif icantly reduced. To investigate whether the reduced circulating IGF-I accou nts for the loss in muscle mass, we increased circulating IGF-I by coinfusi ng 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 deg radation probably via its inhibitory effect on the autocrine IGF-I system.