Angiotensin II directly induces muscle protein catabolism through the ubiquitin–proteasome proteolytic pathway and may play a role in cancer cachexia

Abstract

The ability of angiotensin I (Ang I) and II (Ang II) to induce directly protein degradation in skeletal muscle has been studied in murine myotubes. Angiotensin I stimulated protein degradation with a parabolic dose -response curve and with a maximal effect between 0.05 and 0.1 mM. The effect was attenuated by coincubation with the angiotensin-converting enzyme (ACE) inhibitor imidaprilat, suggesting that angiotensin I stimulated protein degradation through conversion to Ang II. Angiotensin II also stimulated protein breakdown with a similar dose -response curve, and with a maximal effect between 1 and 2.5 mM. Total protein degradation, induced by both Ang I and Ang II, was attenuated by the proteasome inhibitors lactacystin (5 mM) and MG132 (10 mM), suggesting that the effect was mediated through upregulation of the ubiquitin -proteasome proteolytic pathway. Both Ang I and Ang II stimulated an increased proteasome 'chymotrypsin-like' enzyme activity as well as an increase in protein expression of 20S proteasome a-subunits, the 19S subunits MSS1 and p42, at the same concentrations as those inducing protein degradation. The effect of Ang I was attenuated by imidaprilat, confirming that it arose from conversion to Ang II. These results suggest that Ang II stimulates protein degradation in myotubes through induction of the ubiquitin -proteasome pathway. Protein degradation induced by Ang II was inhibited by insulin-like growth factor and by the polyunsaturated fatty acid, eicosapentaenoic acid. These results suggest that Ang II has the potential to cause muscle atrophy through an increase in protein degradation. The highly lipophilic ACE inhibitor imidapril (Vitort) (30 mg kg À1 ) attenuated the development of weight loss in mice bearing the MAC16 tumour, suggesting that Ang II may play a role in the development of cachexia in this model.

Mechanisms of Cancer Cachexia

“…This was confirmed with IGF-I transgenic mice, which overexpress IGF-I in muscle, where wasting was not seen after infusion of ANG II, or the increased mRNA for the ubiquitin ligases atrogin-1 and MuRF1 seen in wild-type mice (246). IGF-I was also effective in attenuating the increased protein degradation and activation of the ubiquitin-proteasome pathway by ANG II in murine myotubes (230), as well as the depression in protein synthesis (222).…”

“…Infusion of ANG II into rats produced a significant decrease in body weight, with the loss of lean body mass being the major contributor to the weight loss (26). This was attributed to an acceleration of total protein breakdown, and in vitro studies using murine myotubes showed ANG II to directly induce muscle protein catabolism through an increase in activity and expression of the ubiquitin-proteasome pathway (230). In vivo studies in rats showed that some of the weight loss derived from an anorexigenic response to ANG II, together with a catabolic effect (26).…”

Proteasome Activity as a Target of Hormone Replacement Therapy–Dependent Plaque Stabilization in Postmenopausal Women

“…However, it is worth noticing that, for statins and antagonists of the rennin-angiotensin system, 2 of the most successful drugs in cardiovascular diseases, an antioxidative and a proteasome inhibitory effect have been described. 32,33 Whether this is an effect that relates to their clinical benefit, however, awaits further investigation. These findings are also potentially important from a practical standpoint, because they raise the interesting possibility that modification of the UPS activity by HRT might provide a novel form of therapy for plaque stabilization of elderly women with atherosclerotic disease and prevention of acute ischemic syndromes.…”

Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients

“…Several potential mediators of the cachectic process, including proteolysis-inducing factor (PIF) and angiotensin II (Ang II), inhibit protein synthesis in skeletal muscle Russell et al, 2006a), and also stimulate degradation, through increased activity and expression of the ubiquitin -proteasome pathway (Lorite et al, 2001;Sanders et al, 2005). We have recently shown a link between the ability of PIF and Ang II to inhibit protein synthesis and increase protein degradation in murine myotubes through the dsRNA-dependent protein kinase (PKR).…”