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Activin Signaling Regulates Autophagy and Cardiac Aging through mTORC2

Kai Chang, Ping Kang, Ying Liu, Kerui Huang, Erika Taylor, Antonia P. Sagona, Ioannis P. Nezis, Rolf Bodmer, Karen Ocorr, Hua Bai
doi: https://doi.org/10.1101/139360
Kai Chang
1Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011, USA
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Ping Kang
1Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011, USA
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Ying Liu
1Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011, USA
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Kerui Huang
1Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011, USA
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Erika Taylor
2Development, Aging, and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92037, USA
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Antonia P. Sagona
3School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK
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Ioannis P. Nezis
3School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK
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Rolf Bodmer
2Development, Aging, and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92037, USA
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Karen Ocorr
2Development, Aging, and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92037, USA
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Hua Bai
1Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011, USA
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  • For correspondence: hbai@iastate.edu
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Abstract

Age-dependent loss of cardiac tissue homeostasis largely impacts heart performance and contributes significantly to cardiovascular diseases later in life. Cellular quality control machinery, such as autophagy/lysosome system, plays a crucial role in maintaining cardiac health and preventing age-induced cardiomyopathy and heart failure. However, how aging alters the autophagy/lysosome system to impact cardiac function remains largely unknown. Here using Drosophila heart as a model system, we show that activin signaling, a member of TGF-beta superfamily, negatively regulates cardiac autophagy and cardiac health during aging. We found that cardiac-specific knockdown of Daw, an activin-like protein in Drosophila, increased cardiac autophagy and prevented age-related cardiac dysfunction, including arrhythmia and bradycardia (slow heart rate). Inhibition of autophagy blocked Daw knockdown-mediated cardioprotection. Consistently, cardiac-specific expression of constitutively activated activin type I receptor Babo disrupted cardiac function at young ages. Intriguingly, the key autophagy regulator, mechanistic target of rapamycin complex 1 (mTORC1), was not involved in activin-mediated autophagy. Instead, activin signaling genetically interacted with Rictor, the key subunit of mTORC2, to regulate autophagy and cardiac aging. Knockdown of Daw increased the mRNA expression of Rictor and the phosphorylation of AKT in fly hearts. Finally, cardiac-specific silencing of Daw not only improved cardiac health, but also prolonged lifespan. Thus, our findings highlight an emerging role of activin signaling and mTORC2 in the regulation of autophagy and cardiac aging.

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Posted October 01, 2018.
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Activin Signaling Regulates Autophagy and Cardiac Aging through mTORC2
Kai Chang, Ping Kang, Ying Liu, Kerui Huang, Erika Taylor, Antonia P. Sagona, Ioannis P. Nezis, Rolf Bodmer, Karen Ocorr, Hua Bai
bioRxiv 139360; doi: https://doi.org/10.1101/139360
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Activin Signaling Regulates Autophagy and Cardiac Aging through mTORC2
Kai Chang, Ping Kang, Ying Liu, Kerui Huang, Erika Taylor, Antonia P. Sagona, Ioannis P. Nezis, Rolf Bodmer, Karen Ocorr, Hua Bai
bioRxiv 139360; doi: https://doi.org/10.1101/139360

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