The rapid loss of
muscle mass, which occurs with disuse and systemically with fasting, cancer and many other diseases, results primarily from accelerated breakdown of
muscle proteins. In atrophying
muscles, the
ubiquitin-proteasome pathway catalyzes the accelerated degradation of
myofibrillar proteins, but the possible importance of the autophagic/
lysosomal pathway in
atrophy has received little attention. Our
prior studies demonstrate that
activation of FoxO
transcription factors is essential for
muscle atrophy, and that activated FoxO3 by itself causes dramatic
atrophy of
muscles and cultured
myotubes via transcription of a set of atrophy-related genes ("atrogenes") including critical
ubiquitin ligases. Using
selective inhibitors, we measured isotopically the actual contribution of
proteasomes and
lysosomes to the FoxO3-induced increase in protein breakdown in
myotubes and found that FoxO3 coordinately activates both
proteolytic systems, but especially
lysosomal proteolysis. Activated FoxO3 stimulates autophagy through a transcription-dependent mechanism and increases the transcription of many autophagy-related genes, which are also induced in
mouse muscles atrophying due to denervation or fasting. Thus, in atrophying
muscles, decreased IGF1-PI3K-Akt signaling stimulates autophagy, not only through
mTOR, but also more slowly by FoxO3-dependent transcription. These findings on
muscle provide the first evidence for coordinate regulation of proteasomal and
lysosomal systems, although in
neuronal and
hepatic cells, FoxO3 stimulates the autophagic process selectively.
