1. ¹Molecular Virology Research Center, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
2. ²Oligos Etc. Inc., Wilsonville, OR, USA

Correspondence: Dr L-Q Sun, Oligos Etc Inc., 9775 SW Commerce Circle C6, PO Box 727, Wilsonville, OR 97070, USA. E-mail: lsun@oligosetc.com; Professor P Tien, Molecular Virology Research Center, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, China. E-mail: tienpo@sun.im.ac.cn

³These two authors contributed equally.

Received 9 April 2007; Revised 22 July 2007; Accepted 1 August 2007; Published online 21 September 2007.

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.