PGC-1α and PGC-1β increase CrT expression and creatine uptake in myotubes via ERRα

Erin L. Brown, Rod J. Snow, Craig R. Wright, Yoshitake Cho, Marita A. Wallace, Anastasia Kralli, Aaron P. Russell

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2937-2943
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1843
Issue number12
DOIs
StatePublished - Dec 2014
Externally publishedYes

Keywords

  • Creatine
  • Creatine transporter
  • ERRα
  • PGC-1α
  • PGC-1β
  • Skeletal muscle

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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