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 autophagy/lysosome system to impact cardiac function remain 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 promotes age-dependent decline of cardiac functions. We found that cardiac-specific knockdown of Daw, an activin-like protein in Drosophila, increased cardiac autophagosome number and prevented age-induced cardiac arrhythmias and diastolic dysfunction. Conversely, cardiac-specific expressed activin type I receptor Babo results in pre-matured cardiac dysfunction at young ages. Although Daw positively modulates mTOR signaling (Mechanistic target of rapamycin, the major negative regulator for autophagy), activation of mTOR through the knockdown of Tsc1 (Tuberous sclerosis protein 1) did not rescue the autophagy and cardiac aging phenotypes in Daw RNAi flies. On the other hand, inhibition of autophagy via chloroquine feeding or Atg1 knockdown attenuated the beneficial effects of Daw RNAi on age-related cardiac arrhythmias. Finally, reduction in cardiac activin signaling prolonged lifespan and improved climbing ability during aging. Thus, our findings highlight the emerging role of activin signaling in mTOR-independent regulation of autophagy and cardiac aging.
