TY - JOUR
T1 - PGC-1α and PGC-1β increase CrT expression and creatine uptake in myotubes via ERRα
AU - Brown, Erin L.
AU - Snow, Rod J.
AU - Wright, Craig R.
AU - Cho, Yoshitake
AU - Wallace, Marita A.
AU - Kralli, Anastasia
AU - Russell, Aaron P.
N1 - Funding Information:
This work was supported by the Centre for Physical Activity and Nutrition Research, Deakin University . YC and AK were supported by the American Heart Association (AHA # 12POST8610009 , 14SDG17790005 ) and NIDDK ( R01DK095686 to AK).
Publisher Copyright:
© 2014 Elsevier B.V.
PY - 2014/12
Y1 - 2014/12
N2 - Intramuscular creatine plays a crucial role in maintaining skeletal muscle energy homeostasis, and its entry into the cell is dependent upon the sodium chloride dependent Creatine Transporter (CrT; Slc6a8). CrT activity is regulated by a number of factors including extra- and intracellular creatine concentrations, hormones, changes in sodium concentration, and kinase activity, however very little is known about the regulation of CrT gene expression. The present study aimed to investigate how Creatine Transporter (CrT) gene expression is regulated in skeletal muscle. Within the first intron of the CrT gene, we identified a conserved sequence that includes the motif recognized by the Estrogen-related receptor α (ERRα), also known as an Estrogen-related receptor response element (ERRE). Additional ERREs confirming to the known consensus sequence were also identified in the region upstream of the promoter. When partnered with peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α) or beta (PGC-1β), ERRα induces the expression of many genes important for cellular bioenergetics. We therefore hypothesized that PGC-1 and ERRα could also regulate CrT gene expression and creatine uptake in skeletal muscle. Here we show that adenoviral overexpression of PGC-1α or PGC-1β in L6 myotubes increased CrT mRNA (2.1 and 1.7-fold, P. <. 0.0125) and creatine uptake (1.8 and 1.6-fold, P. <. 0.0125), and this effect was inhibited with co-expression of shRNA for ERRα. Overexpression of a constitutively active ERRα (VP16-ERRα) increased CrT mRNA approximately 8-fold (P. <. 0.05), resulting in a 2.2-fold (P. <. 0.05) increase in creatine uptake. Lastly, chromatin immunoprecipitation assays revealed that PGC-1α and ERRα directly interact with the CrT gene and increase CrT gene expression.
AB - Intramuscular creatine plays a crucial role in maintaining skeletal muscle energy homeostasis, and its entry into the cell is dependent upon the sodium chloride dependent Creatine Transporter (CrT; Slc6a8). CrT activity is regulated by a number of factors including extra- and intracellular creatine concentrations, hormones, changes in sodium concentration, and kinase activity, however very little is known about the regulation of CrT gene expression. The present study aimed to investigate how Creatine Transporter (CrT) gene expression is regulated in skeletal muscle. Within the first intron of the CrT gene, we identified a conserved sequence that includes the motif recognized by the Estrogen-related receptor α (ERRα), also known as an Estrogen-related receptor response element (ERRE). Additional ERREs confirming to the known consensus sequence were also identified in the region upstream of the promoter. When partnered with peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α) or beta (PGC-1β), ERRα induces the expression of many genes important for cellular bioenergetics. We therefore hypothesized that PGC-1 and ERRα could also regulate CrT gene expression and creatine uptake in skeletal muscle. Here we show that adenoviral overexpression of PGC-1α or PGC-1β in L6 myotubes increased CrT mRNA (2.1 and 1.7-fold, P. <. 0.0125) and creatine uptake (1.8 and 1.6-fold, P. <. 0.0125), and this effect was inhibited with co-expression of shRNA for ERRα. Overexpression of a constitutively active ERRα (VP16-ERRα) increased CrT mRNA approximately 8-fold (P. <. 0.05), resulting in a 2.2-fold (P. <. 0.05) increase in creatine uptake. Lastly, chromatin immunoprecipitation assays revealed that PGC-1α and ERRα directly interact with the CrT gene and increase CrT gene expression.
KW - Creatine
KW - Creatine transporter
KW - ERRα
KW - PGC-1α
KW - PGC-1β
KW - Skeletal muscle
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U2 - 10.1016/j.bbamcr.2014.08.010
DO - 10.1016/j.bbamcr.2014.08.010
M3 - Article
C2 - 25173818
AN - SCOPUS:84907459151
SN - 0167-4889
VL - 1843
SP - 2937
EP - 2943
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 12
ER -