RT Journal Article
SR Electronic
T1 Heart-Specific Activin Signaling Promotes Cardiomyopathy and Organismal Aging through Autophagy Inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 139360
DO 10.1101/139360
A1 Kai Chang
A1 Ping Kang
A1 Ying Liu
A1 Kerui Huang
A1 Erika Taylor
A1 Rolf Bodmer
A1 Karen Ocorr
A1 Hua Bai
YR 2017
UL http://biorxiv.org/content/early/2017/05/31/139360.abstract
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 autophagy/lysosome system to impact cardiac function remain largely unknown. Here using Drosophila model system, we show that cellular autophagic flux and lysosome number decrease in aging heart, which is associated with increased cardiomyopathy and cardiac arrhythmias. Among many known autophagy regulators, activin signaling (a member of TGF-beta superfamily) was identified in our recent study as a negative factor of autophagy and protein homeostasis in flight muscle. In this study, we find that cardiac-specific knockdown of Daw, an activin-like protein in Drosophila, prevents age-dependent increases in cardiac arrhythmias and diastolic dysfunction. Furthermore, cardiac-specific expressed activin type I receptor Babo results in pre-matured cardiac aging phenotypes at young ages. Similar to our previous flight muscle study, Daw silencing strongly promotes early step of autophagy process (i.e. autophagosome formation), and shows less impacts on autophagosome-lysosome fusion. Flies with Daw knockdown also maintain robust autophagic flux in aged fly hearts. Interestingly, reduction in cardiac activin signaling significantly prolongs lifespan and improves the functions of distal tissues (such as age-dependent climbing ability). Thus, our findings highlight the emerging role of activin signaling in autophagic regulation, cardiac aging, as well as systemic control of longevity.