TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2

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dc.contributor.author Chang, Kai
dc.contributor.author Kang, Ping
dc.contributor.author Bai, Hua
dc.contributor.author Liu, Ying
dc.contributor.author Huang, Kerui
dc.contributor.author Miao, Ting
dc.contributor.author Sagona, Antonia
dc.contributor.author Nezis, Ioannis
dc.contributor.author Bodmer, Rolf
dc.contributor.author Ocorr, Karen
dc.contributor.author Bai, Hua
dc.contributor.department Genetics, Development and Cell Biology
dc.date 2020-06-12T15:27:49.000
dc.date.accessioned 2020-06-30T04:02:20Z
dc.date.available 2020-06-30T04:02:20Z
dc.date.copyright Tue Jan 01 00:00:00 UTC 2019
dc.date.issued 2019-01-01
dc.description.abstract <p>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 <em>Drosophila</em> 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 <em>daw</em> 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 <em>daw</em> knockdown flies. Lastly, either <em>daw</em> knockdown or <em>rictor</em> 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.</p>
dc.description.comments <p>This article is published as Chang, Kai, Ping Kang, Ying Liu, Kerui Huang, Ting Miao, Antonia P. Sagona, Ioannis P. Nezis, Rolf Bodmer, Karen Ocorr, and Hua Bai. "TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2." <em>Autophagy</em> (2019). doi: <a href="https://doi.org/10.1080/15548627.2019.1704117">10.1080/15548627.2019.1704117</a>.</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/gdcb_las_pubs/255/
dc.identifier.articleid 1256
dc.identifier.contextkey 18077088
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath gdcb_las_pubs/255
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/37933
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/gdcb_las_pubs/255/2019_Bai_ActivinSignaling.pdf|||Fri Jan 14 22:58:45 UTC 2022
dc.source.uri 10.1080/15548627.2019.1704117
dc.subject.disciplines Cardiovascular Diseases
dc.subject.disciplines Cell Biology
dc.subject.disciplines Developmental Biology
dc.subject.keywords Atg8a
dc.subject.keywords autophagic flux
dc.subject.keywords dawdle
dc.subject.keywords INHB/activin ligand
dc.subject.keywords semi-automatic optical heartbeat analysis (SOHA)
dc.subject.keywords TOR complex 2
dc.title TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2
dc.type article
dc.type.genre article
dspace.entity.type Publication
relation.isAuthorOfPublication ae16dcee-afdf-4805-9590-eb7a0bb1d0f1
relation.isOrgUnitOfPublication 9e603b30-6443-4b8e-aff5-57de4a7e4cb2
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