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2009 Southern Regional Meeting Abstracts
Session: Joint Plenary Poster Session and Reception
SKELETAL MUSCLE-SPECIFIC OVEREXPRESSION OF INSULIN-LIKE GROWTH FACTOR I DECREASES OXIDATIVE STRESS AND PREVENTS ANGIOTENSIN II-INDUCED SKELETAL MUSCLE WASTING: NOVEL POTENTIAL THERAPY TO TREAT CACHEXIA IN CONGESTIVE HEART FAILURE
Semprun-Prieto L1,2, Sukhanov S1, Yoshida T1, Vaughn C1, Delafontaine P1. 1Tulane University, New Orleans, LA and 2Tulane University, New Orleans, LA.
Purpose of Study: Congestive heart failure (CHF) is associated with elevated levels of angiotensin II (ANG) and skeletal muscle wasting (cachexia). We have shown that ANG infusion in FVB mice induces skeletal muscle wasting and increases oxidative stress. Since we also found that insulin-like growth factor I (IGF-1) exerts anti-oxidant effects in a murine model, we hypothesized that skeletal muscle-specific IGF-1 overexpression would decrease ANG-induced muscle wasting and/or oxidative stress.
Methods Used: 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) for 7d. Oxidative stress was assessed in muscle homogenates using superoxide-sensitive dye L-012. Gene expression was measured by RT-PCR.
Summary of Results: ANG decreased skeletal muscle weight in FVB (ANG/SHM, gastrocnemius: 99.8±3.6/122.3±4.2mg; tibialis anterior: 32.0±1.3/41.3±1.3mg; quadriceps: 117.6±6.1/160.6±6.7mg), however no significant muscle wasting was found in ANG-infused MLC. ANG induced leftward shift in myofibers number/size distribution and decreased cross-sectional area (CSA) of type I and II myofibers in FVB (type I, 443±22/528±28 um2; type II, 620±40/835±44 um2) without effect on myofibers distribution and CSA in MLC as detected by immunostaining of gastrocnemius muscle with isoform-specific antibodies. 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) dramatically suppressed ANG-induced superoxides in muscle FVB (91±5% decrease vs. control). ANG II also upregulated NOX4 (a NADPH oxidase subunit) gene 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).
Conclusions: Thus, IGF-1 overexpression suppresses oxidative stress and efficiently blocks skeletal muscle wasting, possibly via inhibition of NADPH oxidase dependent superoxide formation.
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