M. Brink et al., Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I, ENDOCRINOL, 142(4), 2001, pp. 1489-1496
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.