Overexpression of FOXO1 in skeletal muscle does not alter longevity in mice.
Caloric restriction (CR) is the most robust and reproducible intervention that can extend lifespan in rodents. Studies in invertebrates have led to the identification of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signaling pathway, including DAF-16 (C. elegans) and dFOXO (Drosophila). Mice subjected to CR for 8 weeks showed an increase in FOXO1 mRNA and other longevity-related genes: Gadd 45alpha, glutamine synthase, and catalase in skeletal muscle. To investigate whether FOXO1 expression affects longevity in mammals, transgenic mice were studied that over-express FOXO1 in their skeletal muscle (FOXO1 mice), and in which muscle atrophy occurs. FOXO1 mice showed increases in Gadd 45alpha, and glutamine synthase proteins in skeletal muscle. In FOXO1 mice, the phosphorylation/dephosphorylation state of the p70 S6K and 4E-BP1 proteins were not altered, suggesting that translation initiation of protein synthesis might not be suppressed. The lifespan of FOXO1 mice was similar to their wild-type littermates. FOXO1 overexpression could not prevent aging-induced reduction in catalase, CuZu-SOD, and Mn-SOD mRNA in skeletal muscle. These data suggest that an increase in FOXO1 protein and its activation in skeletal muscle does not extend lifespan in mice.
Nutritional Science Program, National Institute of Health and Nutrition, Shinjuku-ku, Tokyo, Japan.
Tsuyoshi
T
Chiba
Yasutomi
Y
Kamei
Takahiko
T
Shimizu
Takuji
T
Shirasawa
Aki
A
Katsumata
Lisa
L
Shiraishi
Satoshi
S
Sugita
Yoshihiro
Y
Ogawa
Shinji
S
Miura
Osamu
O
Ezaki
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D031204:Caloric Restriction; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D005970:Glutamate Synthase / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010442:Peptide Chain Initiation, Translational / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002374:Catalase; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005970:Glutamate Synthase; D009124:Muscle Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D013482:Superoxide Dismutase; C499527:Eif4ebp1 protein, mouse; C467200:Foxo1 protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins