Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.
Skeletal muscle atrophy is a debilitating response to fasting, disuse, cancer, and other systemic diseases. In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy. Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. When Foxo activation is blocked by a dominant-negative construct in myotubes or by RNAi in mouse muscles in vivo, atrogin-1 induction during starvation and atrophy of myotubes induced by glucocorticoids are prevented. Thus, forkhead factor(s) play a critical role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting.
Sandri
Marco
M
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Sandri
Claudia
C
Gilbert
Alex
A
Skurk
Carsten
C
Calabria
Elisa
E
Picard
Anne
A
Walsh
Kenneth
K
Schiaffino
Stefano
S
Lecker
Stewart H
SH
Goldberg
Alfred L
AL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D003001:Cloning, Molecular; D005215:Fasting / Q000378:metabolism; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D005938:Glucocorticoids / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D032342:Muscle Cells / Q000201:enzymology; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034622:RNA Interference; D044843:SKP Cullin F-Box Protein Ligases; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D005938:Glucocorticoids; D007334:Insulin-Like Growth Factor I; D008025:Ligases; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D044843:SKP Cullin F-Box Protein Ligases; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C486692:Fbxo32 protein, rat