Angiotensin II upregulates PP2Calpha and inhibits AMPK signaling and energy balance leading to skeletal muscle wasting
Description
Congestive heart failure (CHF) and chronic kidney disease (CKD) are characterized by chronic elevated levels of angiotensin II (Ang II) and muscle wasting. Ang II causes skeletal muscle wasting by reducing food intake and by enhancing catabolism. The serine/threonine kinase 5'-Adenosine Monophosphate Activated Protein Kinase (AMPK) functions mainly as a sensor of cellular energy status. It is energy sparing and favors ATP generation. We hypothesized that Ang II induces muscle wasting in part by inhibiting AMPK signaling and altering cellular energy balance. Our results show that Ang II infusion in mice reduced gastrocnemius and quadriceps muscle weight by 26% and 23% respectively, while tibialis anterior and soleus muscles were partially resistant to Ang II wasting, exhibiting 9% and 12% reductions in weight respectively. ATP was depleted in skeletal muscle by 45-74%. Further, Ang II upregulated expression of the protein phosphatase PP2Calpha by 2.6 fold and inhibited AMPK phosphorylation and signaling in wasting gastrocnemius muscle. Importantly, the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) restored AMPK activity to levels of pair-fed controls and abrogated Ang II-induced ATP depletion and muscle wasting. Moreover, AICAR activated Akt and inhibited Ang II-induced increases in E3 ubiquitin ligase expression. These results demonstrate critical roles for energy depletion and AMPK inhibition in Ang II-induced skeletal muscle wasting, and suggest a therapeutic potential for AMPK activators in muscle wasting conditions