Abstract 5324: Skeletal Muscle-specific Overexpression of Insulin-like Growth Factor I Suppresses Angiotensin II-induced Oxidative Stress and Prevents Skeletal Muscle Wasting
Congestive heart failure (CHF) is a leading cause of cardiovascular mortality and morbidity and is associated with elevated circulating levels of angiotensin II (ANG) and muscle wasting (cachexia), which is an important predictor of poor outcome. We have shown that ANG infusion in FVB mice reduces skeletal muscle IGF-1 expression, increases oxidative stress and induces skeletal muscle wasting. We hypothesized that skeletal muscle-specific IGF-1 overexpression would decrease ANG-induced oxidative stress and muscle wasting. Mice overexpressing IGF-1 under control of the skeletal muscle-specific type II myosin light chain promoter (MLC) and control mice (FVB) were infused with 1 ug/kg ANG or vehicle (SHM) and were pair-fed for 7 days. ANG decreased skeletal muscle weight in FVB (ANG/SHM, gastrocnemius: 99.8±3.6/122.3±4.2 mg, P< 0.01; tibialis anterior: 32.0±1.3/41.3±1.3 mg, P< 0.05; quadriceps: 117.6±6.1/160.6±6.7 mg, P< 0.05), but not in MLC. ANG induced a leftward shift in myofiber size distribution and decreased cross-sectional area (CSA) of type I and type II myofibers in FVB (ANG/SHM, gastrocnemius, type I, 443±22/528±28 um2; type II, 620±40/835±44 um2) and this effect was completely inhibited in MLC as detected by immunostaining with isoform-specific antibodies. Oxidative stress was assessed in muscle homogenates using superoxide-sensitive dye L-012. ANG increased superoxides in FVB by 67% (228±25 vs. 149±21 RFU/mg protein, p<0.005) but did not significantly increase superoxides in MLC (376±99 vs. 298±81 RFU/mg protein, p=NS). 250 uM Apocynin (a specific NADPH oxidase inhibitor) suppressed ANG-induced superoxides in FVB (91±5% decrease vs. DMSO control). Analysis of NADPH oxidase subunit expression indicated that ANG upregulated NOX4 mRNA expression in skeletal muscle and this effect was greater in FVB (3.6-fold increase, p<0.05) compared to MLC (2.1-fold increase, p=NS, RT-PCR). Thus, IGF-1 overexpression suppresses oxidative stress and efficiently blocks skeletal muscle wasting, possibly via inhibition of ANG-induced NOX4 upregulation and NADPH oxidase-dependent superoxide formation. IGF-1 inhibition of skeletal muscle NADPH oxidase activity could provide a novel approach for the treatment of cachexia.