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Skeletal muscle‐specific overexpression of insulin‐like growth factor I (IGF‐1) decreases oxidative stress and prevents angiotensin II‐induced skeletal muscle wasting: novel potential therapy to treat cachexia in congestive heart failure
Author(s) -
Sukhanov Sergiy,
SemprunPrieto Laura,
Yoshida Tadashi,
Vaughn Charlotte,
Delafontaine Patrick
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.928.6
Subject(s) - endocrinology , medicine , skeletal muscle , nadph oxidase , cachexia , angiotensin ii , nox4 , oxidative stress , chemistry , superoxide , receptor , biochemistry , enzyme , cancer
Congestive heart failure is associated with elevated levels of angiotensin II (ANG) and skeletal muscle wasting (cachexia). We have shown that ANG induces cachexia and increases oxidative stress in FVB mice. Since we also found that IGF‐1 exerts anti‐oxidant effect in a murine model we hypothesized that IGF‐1 overexpression would decrease ANG‐induced cachexia and/or oxidative stress. Mice overexpressing IGF‐1 under control of the skeletal muscle‐specific type II myosin light chain promoter (MLC) and control FVB mice were infused with 1 ug/kg ANG or vehicle (SHM) for 7d. 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 cachexia 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 (immunostaining with isoform‐specific a/b). ANG increased superoxides in FVB by 67±8% (p<0.05) but did not significantly change superoxides in MLC (assay with superoxide‐sensitive dye L‐012). ANG‐induced superoxides were suppressed by apocynin (a specific NADPH oxidase inhibitor) and also ANG increased NOX4 (a NADPH oxidase subunit) expression (RT‐PCR) in both mouse models, however NOX4 upregulation was greater in FVB compared to MLC (3.6‐ vs. 2.1‐fold increase). Thus, IGF‐1 overexpression suppresses oxidative stress and efficiently blocks skeletal muscle wasting, possibly via inhibition of NADPH oxidase‐mediated superoxide formation.