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Cited by 191

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Nitric oxide and AMPK cooperatively regulate PGC-1α in skeletal muscle cells: NO/AMPK-dependent regulation of PGC-1α

Open access
Lira, Vitor A., Brown, Dana L., Lira, Ana K., Kavazis, Andreas N., Soltow, Quinlyn A., Zeanah, Elizabeth H., Criswell, David S.·2010·The Journal of Physiology

Abstract

Nitric oxide (NO) induces mitochondrial biogenesis in skeletal muscle cells via upregulation of the peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). Further, we have shown that nitric oxide interacts with the metabolic sensor enzyme, AMPK. Therefore, we tested the hypothesis that nitric oxide and AMPK act synergistically to upregulate PGC-1α mRNA expression and stimulate mitochondrial biogenesis in culture. L6 myotubes treated with nitric oxide donors, S-nitroso-N-penicillamine (SNAP, 25 μM) or diethylenetriamine-NONO (DETA-NO, 50 μM), exhibited elevated AMPK phosphorylation, PGC-1α mRNA and protein, and basal and uncoupled mitochondrial respiration (P < 0.05). Pre-treatment of cultures with the AMPK inhibitor, Compound C, prevented these effects. Knockdown of AMPKα1 in L6 myotubes using siRNA reduced AMPKα protein content and prevented upregulation of PGC-1α mRNA by DETA-NO. Meanwhile, siRNA knockdown of AMPKα2 had no effect on total AMPKα protein content or PGC-1α mRNA. These results suggest that NO effects on PGC-1α expression are mediated by AMPKα1. Paradoxically, we found that the AMPK-activating compound, AICAR, induced NO release from L6 myotubes, and that AICAR-induced upregulation of PGC-1α mRNA was prevented by inhibition of NOS with N(G)-nitro-L-arginine methyl ester (L-NAME, 1 mM). Additionally, incubation of isolated mouse extensor digitorum longus (EDL) muscles with 2 mM AICAR for 20 min or electrical stimulation (10 Hz, 13 V) for 10 min induced phosphorylation of AMPKα (P < 0.05), which was completely prevented by pre-treatment with the NOS inhibitor, L-N(G)-monomethyl arginine (L-NMMA, 1 mM). These data identify the AMPKα1 isoform as the mediator of NO-induced effects in skeletal muscle cells. Further, this study supports a proposed model of synergistic interaction between AMPK and NOS that is critical for maintenance of metabolic function in skeletal muscle cells.

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Metadata

Authors
Lira, V. A., Brown, D. L., Lira, A. K., Kavazis, A. N., Soltow, Q. A., Zeanah, E. H., & Criswell, D. S.
Venue
The Journal of Physiology
Publisher
Wiley
Published
2010-09-15
Volume
588
Issue
18
Pages
3551-3566
ISSN
0022-3751 (ISSN-L)
OpenAlex
W1542720596
Cited by
191
References
18
FWCI
5.79
Type
journal article
Language
en
Open access
green

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Lira, V. A., Brown, D. L., Lira, A. K., Kavazis, A. N., Soltow, Q. A., Zeanah, E. H., & Criswell, D. S. (2010). Nitric oxide and AMPK cooperatively regulate PGC-1α in skeletal muscle cells: NO/AMPK-dependent regulation of PGC-1α. The Journal of Physiology. https://doi.org/10.1113/jphysiol.2010.194035

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