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1 Faculte de Medicine, Universite Jean Monnet, Saint-Etienne, Cedex, France
2 Biology, York University, Toronto, Ontario, Canada
3 Kinesiology and Health Science, York University, Toronto, Ontario, Canada
4 Biology, York University, Toronto, Ontario, Canada; Kinesiology and Health Science, York University, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: dhood{at}yorku.ca.
Previous work has shown that cytochrome c expression and mitochondrial biogenesis can be invoked by elevated intracellular Ca2+ in muscle cells. To further characterize the potential role of Ca2+ as a messenger involved in mitochondrial biogenesis in skeletal muscle, we determined the effects of the Ca2+ ionophore A23187 on the expression of nuclear- and mitochondrially-encoded genes. Treatment of myotubes with 1 µM A23187 for 48-96 hours increased nuclear-encoded 
-subunit F1ATPase and MDH mRNA levels by 50-100% (p<0.05), but decreased mRNA levels of glutamate dehydrogenase (GDH) by 19% (p<0.05). mRNA levels of the cytochrome oxidase (COX) nuclear-encoded subunits IV, Vb and VIc were unchanged, whereas the mitochondrially-encoded subunits COX II and COX III were decreased by 30% and 70% (p<0.05), respectively. This was paralleled by a 20% decrease (p<0.05) in COX activity. Ruthenium red, an inhibitor of the mitochondrial Ca2+ uniporter, was ineffective in abolishing the effect of A23187 on COX III mRNA level. These data show that cytoplasmic Ca2+ differentially regulates the mRNA level of nuclear and mitochondrial genes. The decline in COX II and III mRNA may be mediated by Tfam, since A23187 modestly reduced Tfam levels by 48 hours. A23187 induced time-dependent increases in Egr-1 mRNA, along with the activation of ERK1/2 and AMPK. MEK inhibition with PD98059 attenuated the increase in Egr-1 mRNA. A23187 also increased Egr-1, SRF and Sp1 protein expression, transcription factors implicated in mitochondrial biogenesis. Egr-1 overexpression increased nuclear-encoded cytochrome c transcriptional activation by 1.5-fold (p<0.05), reduced GDH mRNA by 37% (P<0.05), but had no effect on MDH or -subunit F1ATPase mRNA. These results indicate that changes in intracellular Ca2+ can modify mitochondrial phenotype, in part via the involvement of Egr-1.
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