PT  - JOURNAL ARTICLE
AU  - Kai Chang
AU  - Ping Kang
AU  - Ying Liu
AU  - Kerui Huang
AU  - Erika Taylor
AU  - Antonia P. Sagona
AU  - Ioannis P. Nezis
AU  - Rolf Bodmer
AU  - Karen Ocorr
AU  - Hua Bai
TI  - Activin Signaling Regulates Autophagy and Cardiac Aging through mTORC2
AID  - 10.1101/139360
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 139360
4099  - http://biorxiv.org/content/early/2018/10/01/139360.short
4100  - http://biorxiv.org/content/early/2018/10/01/139360.full
AB  - 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.