Abstract
Foxo-1, a member of the Foxo forkhead type transcription factors, is markedly upregulated in skeletal muscle in energy-deprived states such as fasting, cancer and severe diabetes. In this study, we target the Foxo-1 mRNA in a mouse skeletal myoblast cell line C2C12 and in vivo models of normal and cancer cachexia mice by a Foxo-1 specific RNA oligonucleotide. Our results demonstrate that the RNA oligonucleotide can reduce the expression of Foxo-1 in cells and in normal and cachectic mice, leading to an increase in skeletal muscle mass of the mice. In search for the possible downstream target genes of Foxo-1, we show that when Foxo-1 expression is blocked both in cells and in mice, the level of MyoD, a myogenic factor, is increased while a muscle negative regulator GDF-8 or myostatin is suppressed. Taken together, these results show that Foxo-1 pays a critical role in development of muscle atrophy, and suggest that Foxo-1 is a potential molecular target for treatment of muscle wasting conditions.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lynch GS, Schertzer JD, Ryall JG . Therapeutic approaches for muscle wasting disorders. Pharmacol Ther 2007; 113: 461–872.
Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ, Emanuel BS et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 1993; 5: 230–235.
Kamei Y, Miura S, Suzuki M, Kai Y, Mizukami J, Taniguchi T et al. Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, downregulated Type I (slow twitch/red muscle) fiber genes, and impaired glycemic control. J Biol Chem 2004; 279: 41114–41123.
Bois PR, Grosveld GC . FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts. EMBO J 2003; 22: 1147–1157.
Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NSB, Lam EWF et al. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol Cell Biol 2000; 20: 9138–9148.
Medema RH, Kops GJ, Bos JL, Burgering BMT . AFX-like forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 2000; 404: 782–787.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 1999; 96: 857–868.
Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KWA, Coffer PJ et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 2002; 419: 316–321.
Grobet L, Pirottin D, Farnir F . Modulating skeletal muscle mass by postnatal, muscle-specific inactivation of the GDF-8 gene. Genesis 2003; 35: 227–238.
Lee SJ, McPherron AC . 2001) Regulation of GDF-8 activity and muscle growth. Proc Natl Acad Sci USA 2001; 98: 9306–9311.
Reisz-Porszasz S, Bhasin S, Artaza JN, Shen R, Sinha-Hikim I, Hogue A et al. Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of GDF-8. Am J Physiol Endocrinol Metab 2003; 285: E876–E888.
Wehling M, Cai B, Tidball JG . Modulation of GDF-8 expression during modified muscle use. FASEB J 2000; 14: 103–110.
Baracos VE, DeVivo C, Hoyle DH, Goldberg AL . Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma. Am J Physiol 1995; 268: E996–E1006.
Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004; 117: 399–412.
Bogdanovich S, Krag TO, Barton ER, Morris LD, Whittemore L, Ahima RS et al. Functional improvement of dystrophic muscle by GDF-8 blockade. Nature 2002; 28: 418–421.
Joulia D, Bernardi H, Garandel V, Rabenoelina F, Vernus B, Cabello G . Mechanisms involved in the inhibition of myoblast proliferation and differentiation by GDF-8. Exp Cell Res 2003; 286: 263–275.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Liu, CM., Yang, Z., Liu, CW. et al. Effect of RNA oligonucleotide targeting Foxo-1 on muscle growth in normal and cancer cachexia mice. Cancer Gene Ther 14, 945–952 (2007). https://doi.org/10.1038/sj.cgt.7701091
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.cgt.7701091
Keywords
This article is cited by
-
Molecular mechanisms of exercise contributing to tissue regeneration
Signal Transduction and Targeted Therapy (2022)
-
Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia – can findings from animal models be translated to humans?
BMC Cancer (2016)
-
Comparative transcriptome profiling of longissimus muscle tissues from Qianhua Mutton Merino and Small Tail Han sheep
Scientific Reports (2016)
-
Postsurgical Acute Phase Reaction is Associated with Decreased Levels of Circulating Myostatin
Inflammation (2015)
-
Genome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexia
BMC Cancer (2014)