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TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2 Autophagy
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Chang, Kai, Kang, Ping, Liu, Ying, Huang, Kerui, Miao, Ting, Taylor, Erika, Sagona, Antonia P., Nezis, Ioannis P., Bodmer, Rolf, Ocorr, Karen and Bai, Hua (2020) TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2 Autophagy. Autophagy . doi:10.1080/15548627.2019.1704117 (In Press)
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Official URL: https://doi.org/10.1080/15548627.2019.1704117
Abstract
Age-related impairment of macroautophagy/autophagy and loss of cardiac tissue homeostasis contribute significantly to cardiovascular diseases later in life. MTOR (mechanistic target of rapamycin kinase) signaling is the most well-known regulator of autophagy, cellular homeostasis, and longevity. The MTOR signaling consists of two structurally and functionally distinct multiprotein complexes, MTORC1 and MTORC2. While MTORC1 is well characterized but the role of MTORC2 in aging and autophagy remains poorly understood. Here we identified TGFB-INHB/activin signaling as a novel upstream regulator of MTORC2 to control autophagy and cardiac health during aging. Using Drosophila heart as a model system, we show that cardiac-specific knockdown of TGFB-INHB/activin-like protein daw induces autophagy and alleviates age-related heart dysfunction, including cardiac arrhythmias and bradycardia. Interestingly, the downregulation of daw activates TORC2 signaling to regulate cardiac autophagy. Activation of TORC2 alone through overexpressing its subunit protein rictor promotes autophagic flux and preserves cardiac function with aging. In contrast, activation of TORC1 does not block autophagy induction in daw knockdown flies. Lastly, either daw knockdown or rictor overexpression in fly hearts prolongs lifespan, suggesting that manipulation of these pathways in the heart has systemic effects on longevity control. Thus, our studies discover the TGFB-INHB/activin-mediated inhibition of TORC2 as a novel mechanism for age-dependent decreases in autophagic activity and cardiac health.
| Item Type: | Journal Article | |||||||||||||||||||||
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| Subjects: | R Medicine > RC Internal medicine | |||||||||||||||||||||
| Divisions: | Faculty of Science > Life Sciences (2010- ) | |||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Cardiovascular system -- Diseases, Cardiovascular diseases in old age, Rapamycin, Cardiovascular system -- Diseases -- Treatment., Geriatric cardiology | |||||||||||||||||||||
| Journal or Publication Title: | Autophagy | |||||||||||||||||||||
| Publisher: | Taylor & Francis | |||||||||||||||||||||
| ISSN: | 1554-8627 | |||||||||||||||||||||
| Official Date: | 2020 | |||||||||||||||||||||
| Dates: |
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| Date of first compliant deposit: | 12 December 2019 | |||||||||||||||||||||
| DOI: | 10.1080/15548627.2019.1704117 | |||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||
| Publication Status: | In Press | |||||||||||||||||||||
| Access rights to Published version: | Open Access | |||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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