Abstract 15956: Angiotensin II Disrupts Skeletal Muscle Energy Balance and AMP-Activated Protein Kinase Activation: Implication for Mechanisms of Muscle Wasting in Congestive Heart Failure
Congestive heart failure (CHF) is accompanied by elevated circulating angiotensin II (AngII) and skeletal muscle wasting, which correlates to poor outcome. This study tested the hypothesis that AngII reduces cellular energy stores in skeletal muscle, and characterized the mechanisms involved in the contribution of energy depletion to AngII-induced cachexia.
Methods: FVB mice were sham-infused, AngII infused (1ug/kg/min), or sham-infused, pair-fed (PF, to control for changes in food intake). Mitochondria were quantified via real-time PCR and MitoTracker® staining. Mitochondrial activity was assessed with Cytochrome C Oxidase (COX) Activity Assay. Energy availability was assayed via an ADP/ATP Ratio Assay Kit. AMPK activation was measured with SDS-PAGE and Western Blotting.
Results: AngII reduced mitochondrial content after 4 days in tibialis anterior (TA) by 55% (p<0.01), and there was an apparent compensatory 86% increase (p<0.05) in COX activity. These effects were independent of food intake. No changes in mitochondrial content were observed in gastrocnemius (Gas) muscles; however, we found a 47% reduction (p<0.05) in mitochondrial activity in response to AngII in Gas. Both muscles displayed a 70–80% reduction (p<0.001) in ATP and a 3–4 fold increase (p<0.05) in ADP/ATP ratio with AngII. In response to lowered cellular energy availability in TA, AMPK activation was increased in PF mice and in AngII mice by 2 fold (p<0.005) and 4 fold (p<0.00001) respectively, compared to ad-libitum fed sham mice. Interestingly in Gas, rather than further activating AMPK, AngII actually blocked the 2 fold PF-induced AMPK phosphorylation (p<0.005).
Conclusions: AngII reduces skeletal muscle mitochondrial content or activity, ultimately leading to a major reduction in ATP availability. Interestingly, TA is more resistant to AngII-induced wasting than Gas. Our data suggest that AMPK is performing its intended biological function in TA, with its activation compensating for reduced energy availability. The failure of Gas to react in a similar manner to the energy imbalance may partially explain why this tissue is more sensitive to AngII induced wasting than is TA. These findings are highly relevant to mechanisms of muscle wasting that are a hallmark of advanced CHF.
- © 2010 by American Heart Association, Inc.