Effect of RNA oligonucleotide targeting Foxo-1 on muscle growth in normal and cancer cachexia mice.
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.
Liu
C-M
CM
Molecular Virology Research Center, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Yang
Z
Z
Liu
C-W
CW
Wang
R
R
Tien
P
P
Dale
R
R
Sun
L-Q
LQ
D000818:Animals; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D017570:MyoD Protein / Q000096:biosynthesis / Q000235:genetics; D032446:Myoblasts / Q000378:metabolism*; D055435:Myostatin; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C525912:Mstn protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D055435:Myostatin; D020320:Oligoribonucleotides, Antisense; D016212:Transforming Growth Factor beta