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AMP‐activated protein kinase‐regulated activation of the PGC‐1α promoter in skeletal muscle cells
Author(s) -
Irrcher Isabella,
Kirwan Angie F.,
Hood David A.
Publication year - 2006
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.20.4.a389-a
Subject(s) - ampk , microbiology and biotechnology , skeletal muscle , mitochondrial biogenesis , chemistry , promoter , biology , protein kinase a , kinase , gene expression , gene , mitochondrion , biochemistry , endocrinology
PGC‐1α is an important regulator of mitochondrial biogenesis in skeletal muscle. However, the transcriptional mechanisms controlling PGC‐1α expression in muscle remain to be clearly defined. We have isolated the proximal 2kb sequence of the PGC‐1α promoter from human genomic DNA. Analysis reveals that it contains putative binding sites for Sp1, ATF2/CREB, FKHR, GATA, SRF, MEF2, p53 and NF‐κB as well as multiple E Boxes. Using truncated deletions of the PGC‐1α promoter, we investigated the effect of AMPK activation by AICAR, a known mitochondrial biogenesis‐stimulating agent. AICAR treatment (1mM, 24hrs) increased promoter activity within the 848bp fragment of the PGC‐1α promoter activity by 3.4‐fold (p<0.001) in C 2 C 12 muscle cells. This occurred concomitantly with 1.8‐ (p<0.05) and 2.2‐fold (p<0.05) increases in GATA‐EBox DNA‐binding and PGC‐1α mRNA expression, respectively. The AICAR effect, which is mediated via overlapping GATA/EBox binding sites, requires the cooperative actions of GATA‐4 and USF‐1. GATA‐4 overexpression increased PGC‐1α promoter activity 3.2‐fold (p<0.05), and was further enhanced by 1.4‐fold in the presence of AICAR. Our data define a novel pathway by which AMPK activation regulates PGC‐1α promoter activity via GATA‐4 and USF‐1, ultimately resulting in the induction of PGC‐1α mRNA expression. They also suggest that the modulation of the AMPK signaling pathway via GATA‐4 and/or USF‐1 could represent a potential therapeutic target to control PGC‐1α expression in skeletal muscle. This work was funded by NSERC and CIHR.