Nuclear AMPK regulated CARM1 stabilization impacts autophagy in aged heart.
Senescence-associated autophagy downregulation leads to cardiomyocyte dysfunction. Coactivator-associated arginine methyltransferase 1 (CARM1) participates in many cellular processes, including autophagy in mammals. However, the effect of CARM1 in aging-related cardiac autophagy decline remains undefined. Moreover, AMP-activated protein kinase (AMPK) is a key regulator in metabolism and autophagy, however, the role of nuclear AMPK in autophagy outcome in aged hearts still unclear. Hers we identify the correlation between nuclear AMPK and CARM1 in aging heart. We found that fasting could promote autophagy in young hearts but not in aged hearts. The CARM1 stabilization is markedly decrease in aged hearts, which impaired nucleus TFEB-CARM1 complex and autophagy flux. Further, S-phase kinase-associated protein 2(SKP2), responsible for CARM1 degradation, was increased in aged hearts. We further validated that AMPK dependent FoxO3 phosphorylation was markedly reduced in nucleus, the decreased nuclear AMPK-FoxO3 activity fails to suppress SKP2-E3 ubiquitin ligase. This loss of repression leads to The CARM1 level and autophagy in aged hearts could be restored through AMPK activation. Taken together, AMPK deficiency results in nuclear CARM1 decrease mediated in part by SKP2, contributing to autophagy dysfunction in aged hearts. Our results identified nuclear AMPK controlled CARM1 stabilization as a new actor that regulates cardiac autophagy.
Department of Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Chen
C
Li
Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Lu
L
Yu
Department of Physiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Han
H
Xue
Department of Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Zheng
Z
Yang
Department of Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China; Department of Physiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Yue
Y
Yin
Department of Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Bo
B
Zhang
Department of Cardiovascular Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: chenmai77@hotmail.com.
Mai
M
Chen
Department of Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China; Department of Physiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China. Electronic address: hengma@fmmu.edu.cn.
Heng
H
Ma
D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D005215:Fasting; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D061251:Primary Cell Culture; D055550:Protein Stability; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D044786:S-Phase Kinase-Associated Proteins; C484068:Tcfeb protein, mouse; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D044767:Ubiquitin-Protein Ligases; D055372:AMP-Activated Protein Kinases
AMP-Activated protein kinase; Aging; Autophagy; Coactivator-associated arginine methyltransferase 1; SKP2containing SCF (SKP1-cullin1-F-box protein) E3 ubiquitin ligase