HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Kraft, C. S. Articles by Moyes, C. D. Search for Related Content PubMed PubMed Citation Articles by Kraft, C. S. Articles by Moyes, C. D.

CELLULAR METABOLISM

Control of mitochondrial biogenesis during myogenesis

Departments of Biology¹ and Biochemistry,² Queen's University, Kingston, Ontario, Canada

Submitted 15 September 2005 ; accepted in final form 16 November 2005

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-2 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 (PPAR) mRNA levels increased almost 10-fold, the activity of a PPAR reporter was unchanged during myogenesis. The PPAR coactivator PPAR- coactivator-1 (PGC1), a master controller of mitochondrial biogenesis, was not expressed at detectable levels. However, the mRNA for both PGC1-related coactivator and PGC1 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 (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.

citrate synthase; muscle; transcription factor; coactivator; metabolism

This article has been cited by other articles:

				V. E. Jahnke, O. Sabido, and D. Freyssenet Control of mitochondrial biogenesis, ROS level, and cytosolic Ca2+ concentration during the cell cycle and the onset of differentiation in L6E9 myoblasts Am J Physiol Cell Physiol, May 1, 2009; 296(5): C1185 - C1194. [Abstract] [Full Text] [PDF]

				J. Chen, X. Shi, R. Padmanabhan, Q. Wang, Z. Wu, S. C. Stevenson, M. Hild, D. Garza, and H. Li Identification of novel modulators of mitochondrial function by a genome-wide RNAi screen in Drosophila melanogaster Genome Res., January 1, 2008; 18(1): 123 - 136. [Abstract] [Full Text] [PDF]

				L. Vergani, A. Malena, P. Sabatelli, E. Loro, L. Cavallini, P. Magalhaes, L. Valente, F. Bragantini, F. Carrara, B. Leger, et al. Cultured muscle cells display defects of mitochondrial myopathy ameliorated by anti-oxidants Brain, October 1, 2007; 130(10): 2715 - 2724. [Abstract] [Full Text] [PDF]