Degree Type

Thesis

Date of Award

2020

Degree Name

Doctor of Philosophy

Department

Genetics, Development and Cell Biology

Major

Genetics and Genomics

First Advisor

Hua Bai

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death, especially in the elderly. Dysregulation of longevity pathways, tissue homeostasis, and energy metabolism impose stress on cardiovascular function, significantly fostering premature cardiovascular aging. Therefore, understanding the molecular basis of the above regulation is crucial to improve cardiac health during aging. The MTOR (mechanistic target of rapamycin kinase) signaling, as a longevity pathway, is the master regulator of cellular homeostasis, metabolism, and longevity. MTOR signaling functions through two structurally and functionally distinct multiprotein complexes, MTORC1 and MTORC2. Unlike MTORC1, the regulation of MTORC2 is less studied. 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 showed that cardiac-specific knockdown of TGFB-INHB/activin-like protein daw maintained the intact cardiac autophagic flux and cardiac contractile function in aged flies. Interesting, MTORC2, instead of MTORC1, has been shown to require for this daw-regulated autophagy and cardiac function. Specifically, the reduction of MTORC2 by knocking down its subunit rictor abolished the increased autophagy and beneficial cardiac effects caused by daw knockdown. Furthermore, activation of MTORC2 alone through rictor overexpression is sufficient to promote autophagic flux and preserves cardiac function with aging, suggesting a positive role of MTORC2 in regulating autophagy and cardiac function. Lastly, either daw knockdown or rictor overexpression in fly hearts prolongs lifespan, suggesting that manipulating these pathways in the heart has systemic effects on longevity control. Thus, our studies discover the TGFB-INHB/activin-mediated inhibition of MTORC2 as a novel mechanism for age-dependent decreases in autophagic activity and cardiac health.

MTOR pathway has also been previously shown to regulate the high-fat diet (HFD)-induced obesity and heart dysfunction in Drosophila. Our studies suggest that MTORC2 could protect the heart under HFD feeding. Upon five days of HFD feeding, the heart exhibits contractile dysfunction and altered mitochondrial physiology, including mitochondrial fragmentation, loss of mitochondrial membrane potential, and mitochondrial calcium overload. We also observed that the activity of MTORC2 in the heart is reduced upon five days of HFD feeding. In line with this finding, the flies with cardiac-specific MTORC2 reduction by rictor knockdown mimic HFD-induced cardiac and mitochondrial dysfunction even on a normal diet. Conversely, cardiac-specific activation of MTORC2 by overexpressing rictor rescued the above HFD-induced cardiac and mitochondrial dysfunction, suggesting that MTORC2 provides cardioprotection against HFD.

Collectively, our studies identified the novel role of MTORC2 in regulating cardiovascular function, possibly through mediating autophagy, mitochondrial function during aging, and/or under HFD-induced metabolic stress.

DOI

https://doi.org/10.31274/etd-20210114-24

Copyright Owner

Kai Chang

Language

en

File Format

application/pdf

File Size

174 pages

Share

COinS