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Control of mitochondrial biogenesis during myogenesis
- Source :
- American journal of physiology. Cell physiology. 290(4)
- Publication Year :
- 2006
-
Abstract
- We used expression and reporter gene analysis to understand how changes in transcription factors impinge on mitochondrial gene expression during myogenesis of cultured murine myoblasts (C2C12 and Sol8). The mRNA levels for nuclear respiratory factor-1 (NRF-1) and NRF-2alpha increased 60% by the third day of myogenesis, whereas NRF-1 and NRF-2 reporter gene activity increased by fivefold over the same period. Although peroxisome proliferator activated receptor (PPARalpha) mRNA levels increased almost 10-fold, the activity of a PPAR reporter was unchanged during myogenesis. The PPAR coactivator PPAR-gamma coactivator-1alpha (PGC1alpha), a master controller of mitochondrial biogenesis, was not expressed at detectable levels. However, the mRNA for both PGC1alpha-related coactivator and PGC1beta was abundant, with the latter increasing by 50% over 3 days of differentiation. We also conducted promoter analysis of the gene for citrate synthase (CS), a common mitochondrial marker enzyme. The proximal promoter ( approximately 2,100 bp) of the human CS lacks binding sites for PPAR, NRF-1, or NRF-2. Deletion mutants, a targeted mutation, and an Sp1 site-containing reporter construct suggest that changes in Sp1 regulation also participate in mitochondrial biogenesis during myogenesis. Because most mitochondrial genes are regulated by PPARs, NRF-1, and/or NRF-2, we conducted inhibitor studies to further support the existence of a distinct pathway for CS gene regulation in myogenesis. Although both LY-294002 (a phosphatidylinositol 3-kinase inhibitor) and SB-203580 (a p38-MAPK inhibitor) blocked myogenesis (as indicated by creatine phosphokinase activity), only SB-203580 prevented the myogenic increase in cytochrome oxidase activity, whereas only LY-294002 blocked the increase in CS (enzyme and reporter gene activities). Collectively, these studies help delineate the roles of some transcriptional regulators involved in mitochondrial biogenesis associated with myogenesis and underscore an import role for posttranscriptional regulation of transcription factor activity.
- Subjects :
- Physiology
NF-E2-Related Factor 2
Sp1 Transcription Factor
Peroxisome Proliferator-Activated Receptors
NF-E2-Related Factor 1
Citrate (si)-Synthase
Biology
Muscle Development
Cell Line
Myoblasts
Mice
Genes, Reporter
Coactivator
Animals
Humans
Transcription factor
Regulation of gene expression
Reporter gene
Myogenesis
Cell Differentiation
Cell Biology
Molecular biology
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Mitochondria
Genes, Mitochondrial
Mitochondrial biogenesis
Gene Expression Regulation
Trans-Activators
PPARGC1A
C2C12
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 03636143
- Volume :
- 290
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- American journal of physiology. Cell physiology
- Accession number :
- edsair.doi.dedup.....b1d0cf1355c960bf28fb6f35986d3dc6