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This Article Full Text Full Text (PDF) Supplemental Figures and Tables All Versions of this Article: 297/3/C548    most recent 00502.2008v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by McLoughlin, T. J. Articles by Esser, K. A. PubMed PubMed Citation Articles by McLoughlin, T. J. Articles by Esser, K. A.

MUSCLE CELL BIOLOGY AND CELL MOTILITY

FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner

¹Department of Kinesiology, University of Toledo, Toledo, Ohio; ²Department of Kinesiology, University of Illinois at Chicago, ³Medical Research Unit, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois; and ⁴Department of Physiology, University of Kentucky, Lexington, Kentucky

Submitted 29 September 2008 ; accepted in final form 22 June 2009

Recent studies indicate that FoxO transcription factors play an important role in promoting muscle atrophy. To study mechanisms mediating effects of FoxO proteins on muscle wasting, FoxO1-estrogen receptor fusion proteins that are activated by treatment with 4-hydroxytamoxifen (4-OH-T) were stably transfected in C₂C₁₂ skeletal myoblasts using the pBABE retroviral system and grown into multinucleated skeletal myotubes. Activation of FoxO1 resulted in significant muscle atrophy, which was accompanied by DNA fragmentation, evidenced by terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling. Cells expressing a DNA-binding-deficient form of FoxO1 also exhibited significant atrophy on FoxO1 activation but no hallmark signs of apoptosis. FoxO1 activation resulted in a significant increase in muscle atrophy F-box (MAFbx)/atrogin-1, muscle-specific RING finger protein 1 (MuRF-1), and Bcl-2-interacting mediator of cell death (Bim) gene expression, with no significant increase in Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNip3) gene expression. Although the ability of FoxO1 to induce MuRF-1 gene expression appeared to be independent of DNA binding, expression of MAFbx/atrogin-1 and Bim was significantly blunted in cells expressing DNA-binding-deficient FoxO1. BNip3 gene expression was significantly elevated in DNA-binding-deficient mutant cells. These findings indicate that FoxO1 promotes skeletal muscle atrophy through induction of proteolytic and apoptotic machinery via DNA-binding-dependent and -independent mechanisms.

atrophy; MAFbx/atrogin-1; Bim; BNip3; terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling