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Glucocorticoids attenuate calcineurin signaling and PGC‐1α expression in muscle during diabetes and kidney disease
Author(s) -
Price Russ,
Zheng Bin,
Gooch Jennifer
Publication year - 2012
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.26.1_supplement.1144.15
Subject(s) - endocrinology , calcineurin , medicine , mef2 , cytosol , muscle atrophy , skeletal muscle , signal transduction , chemistry , biology , gene expression , microbiology and biotechnology , biochemistry , gene , enzyme , transplantation , enhancer
Reduced expression of PGC‐1α has been linked to skeletal muscle atrophy in chronic diseases. We previously found that diabetes (DM) and chronic kidney disease (CKD) decrease calcineurin (Cn) phosphatase activity; signaling through its downstream effectors MEF2 and NFATc; and PGC‐1α. Since glucocorticoids are elevated in both conditions and required for muscle atrophy, we investigated if they mediate the changes in Cn signaling and PGC‐1α expression seen in CKD and DM. L6 myotubes were treated with dexamethasone (DEX; 100 nM) to evaluate changes in Cn signaling. Levels of the Cn A catalytic subunit (CnA), NFATc3, and MEF2 were evaluated by Western blot analysis of cytosolic and nuclear cell fractions. NFATc3 and MEF2 proteins were significantly reduced (P<0.05) in the nuclear fraction of cells treated with DEX for 1 hour. CnA is a known substrate of the atrophy‐related MAFbx/atrogin‐1 E3 ubiquitin ligase protein. It was unchanged in both the cytosol and nucleus after ≤ 1 h of DEX but Cn activity in cells was reduced by 28%. In contrast, nuclear CnA was decreased ~50% after 48 h of DEX. Chronic DEX treatment also suppressed the levels of MRF4 and MCIP1.4 mRNA, respective gene targets of MEF2 and NFATc, as well as PGC‐1α expression, as evaluated using a PGC‐1α‐luciferase reporter gene. Our results indicate that glucocorticoids mediate the changes in Cn signaling and PGC‐1α during chronic diseases.