Department of Genetics, Development and Cell Biology – Iowa State University
Host: Kristen Johansen
"Mechanisms of Cardiac Aging: A Tale of Two mTOR Complexes"
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. Using Drosophila heart as a model system, we found that activin signaling, a member of TGF-beta superfamily, negatively regulates cardiac autophagy and promotes age-dependent decline of cardiac functions. Cardiac-specific knockdown of Daw, an activin-like protein in Drosophila, increased cardiac autophagosome number and prevented age-induced cardiac arrhythmia.
Given that mechanistic target of rapamycin complex 1 (mTORC1) is the major negative regulator of autophagy, we predicted that Daw would regulate autophagosome formation through mTORC1. Intriguingly, we found that autophagic induction and cardiac aging in Daw knockdown flies was unaffected by activation of mTORC1. Instead, Daw genetically interacted Rictor, the key subunit of mTORC2, to regulate cardiac autophagy. We also showed that activin signaling and mTORC2/Rictor oppositely regulate basal autophagy, while both pathways played no role in nutrition-related autophagic activation. In addition, heart functional analysis revealed that activation of mTORC1 did not result in accelerated cardiac aging as predicted, whereas either mTORC2 inhibition or activin activation promotes cardiac aging. Thus, our studies uncovered the distinct roles of two mTOR complexes during cardiac aging, and highlight an emerging role of activin signaling and mTORC2 in the regulation of autophagy and tissue homeostasis.
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