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CELLULAR AND MITOCHONDRIAL METABOLISM

Interactions between ROS and AMP kinase activity in the regulation of PGC-1 transcription in skeletal muscle cells

¹School of Kinesiology and Health Science, ²Department of Biology, and ³Muscle Health Research Centre, York University, Toronto, Ontario, Canada

Submitted 25 June 2007 ; accepted in final form 28 October 2008

Reactive oxygen species (ROS) play an important role in cellular function via the activation of signaling cascades. ROS have been shown to affect mitochondrial biogenesis, morphology, and function. Their beneficial effects are likely mediated via the upregulation of transcriptional regulators such as peroxisome proliferator-activated receptor- coactivator-1 protein- (PGC-1). However, the ROS signals that regulate PGC-1 transcription in skeletal muscle are not understood. Here we examined the effect of H₂O₂ on the regulation of PGC-1 expression, and its relationship to AMPK activation. We demonstrate that 24 h of exogenous H₂O₂ treatment increased PGC-1 promoter activity and mRNA expression. Both effects were blocked with the addition of N-acetylcysteine, a ROS scavenger. These effects were mediated, in part, via upstream stimulatory factor-1/Ebox DNA binding and involved 1) interactions with downstream sequences and 2) the activation of AMPK. Elevated ROS led to the activation of AMPK, likely via a decline in ATP levels. The activation of AMPK using 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside increased PGC-1 promoter activity and mRNA levels but reduced ROS production. Thus the net effect of AMPK activation on PGC-1 expression was a result of increased transcriptional activation, counterbalanced by reduced ROS production. The effects of H₂O₂ on PGC-1 expression differed depending on the level of ROS within the cell. Low levels of ROS result in reduced PGC-1 mRNA in the absence of an effect on PGC-1 promoter activation. In contrast, elevated levels of H₂O₂ induce PGC-1 transcription indirectly, via AMPK activation. These data identify unique interactions between ROS and AMPK activation on the expression of PGC-1 in muscle cells.

C₂C₁₂ cells; mitochondrial biogenesis; muscle gene expression; adenosine 5'-monophosphate kinase; upstream stimulatory factor-1; reactive oxygen species; peroxisome proliferator-activated receptor- coactivator-1 protein-

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