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Regulation of PGC‐1α expression in skeletal muscle: Comparison of the effects of calcineurin and PKA/cAMP signaling on PGC‐1α transcription
Author(s) -
Price Russ,
Zheng Bin,
Li Haiyan,
WoodworthHobbs Myra,
Gooch Jennifer
Publication year - 2011
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.25.1_supplement.1059.15
Subject(s) - creb , nfat , transcription factor , transfection , mef2 , forskolin , calcineurin , microbiology and biotechnology , luciferase , biology , signal transduction , reporter gene , phosphorylation , endocrinology , chemistry , medicine , gene expression , biochemistry , gene , enhancer , stimulation , transplantation
PGC‐1α controls energy metabolism in muscle cells. Its expression is regulated by the calcium/calcineurin(Cn)/MEF2/NFAT and cAMP/CREB signaling pathways in other cell types. Earlier, we found that atrophy‐inducing conditions reduce PGC‐1α expression in muscle. Under the same conditions, activity of the Cn/MEF2/NFAT pathway was diminished whereas CREB phosphorylation was elevated. These findings suggest that the regulation of PGC‐1α expression by CREB, but not Cn, is dysfunctional in muscle. Therefore, we examined how cAMP/CREB and Cn affect the activity of PGC‐1α‐ and CRE‐luciferase (Luc) reporter genes in L6 myotubes. Cells were transfected with PGC‐1α‐Luc or PGC‐1αΔCRE‐Luc which lacks a CRE binding site. Basal activity of PGC‐1αΔCRE‐Luc was 72% less than for PGC‐1α‐Luc (P<0.01). Treating cells with forskolin (FSK) to raise cAMP did not increase luciferase activity from either PGC‐1α reporter whereas FSK increased the activity of CRE‐Luc 931% (P<0.001). These results suggest that CREB regulates PGC‐1α transcription but that CREB activation alone is insufficient to drive PGC‐1α expression. In contrast, co‐transfection of constitutively‐activated Cn increased PGC‐1α‐Luc activity 211% (P<0.005) but had no effect on CRE‐Luc activity. In summary, our results indicate that abnormalities in both pathways may contribute to the reduced PGC‐1α expression during muscle atrophy. Supported by NIDDK/NIH.