FoxO transcription factors promote autophagy in cardiomyocytes.
In the heart, autophagy is required for normal cardiac function and also has been implicated in cardiovascular disease. FoxO transcription factors promote autophagy in skeletal muscle and have additional roles in regulation of cell size, proliferation, and metabolism. Here we investigate the role of FoxO transcription factors in regulating autophagy and cell size in cardiomyocytes. In cultured rat neonatal cardiomyocytes, glucose deprivation leads to decreased cell size and induction of autophagy pathway genes LC3, Gabarapl1, and Atg12. Likewise, overexpression of either FoxO1 or FoxO3 reduces cardiomyocyte cell size and induces expression of autophagy pathway genes. Moreover, inhibition of FoxO activity by dominant negative FoxO1 (Delta256) blocks cardiomyocyte cell size reduction upon starvation, suggesting the necessity of FoxO function in cardiomyocyte cell size regulation. Under starvation conditions, endogenous FoxO1 and FoxO3 are localized to the nucleus and bind to promoter sequences of Gabarapl1 and Atg12. In vivo studies show that cellular stress, such as starvation or ischemia/reperfusion in mice, results in induction of autophagy in the heart with concomitant dephosphorylation of FoxO, consistent with increased activity of nuclear FoxO transcription factors. Together these results provide evidence for an important role for FoxO1 and FoxO3 in regulating autophagy and cell size in cardiomyocytes.
Sengupta
Arunima
A
Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Center, Cincinnati, Ohio 45229.
Molkentin
Jeffery D
JD
Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Center, Cincinnati, Ohio 45229.
Yutzey
Katherine E
KE
Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Center, Cincinnati, Ohio 45229. Electronic address: katherine.yutzey@cchmc.org.
D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000502:physiology*; D000071192:Autophagy-Related Protein 12; D000071190:Autophagy-Related Protein 8 Family; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013217:Starvation; D000071161:Forkhead Box Protein O1
D000071192:Autophagy-Related Protein 12; D000071190:Autophagy-Related Protein 8 Family; D002352:Carrier Proteins; D003470:Culture Media; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; C491971:Atg12 protein, mouse; C499515:FOXO3 protein, rat; C407740:Gabarapl2 protein, mouse; C480860:Map1lc3b protein, mouse; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
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