Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle.
The balance between synthesis and degradation of intracellular components determines the overall muscle fiber size. Muscle atrophy occurs when the degradation rate is higher than the synthesis rate, for example during disuse, fasting or systemic diseases such as diabetes, cancer and renal failure. The two main catabolic systems that are activated during atrophy are the ubiquitin-proteasome and the autophagy-lysosome pathways. FoxO3 transcription factor causes marked atrophy in adult skeletal muscle and induces the muscle-specific ubiquitin ligase Atrogin-1/MAFbx.(1) In addition, we recently reported that FoxO3 is necessary and sufficient for the induction of autophagy in skeletal muscle.(2) Transcription of autophagy related genes, such as LC3B and Bnip3, is activated during fasting and is mediated by FoxO3. In particular, Bnip3 induces autophagosome formation and is responsible for the induction of autophagy by FoxO3. Surprisingly, rapamycin is not able to induce autophagy in skeletal muscle in vivo, indicating that the Akt-FoxO axis, rather than the Akt-mTOR pathway, is involved in this process. Here we discuss the major implications of our recent work.
Mammucari
Cristina
C
Venetian Institute of Molecular Medicine, Padova, Italy.
Schiaffino
Stefano
S
Sandri
Marco
M
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008869:Microtubule-Associated Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases