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

Chang, Kai; Kang, Ping; Liu, Ying; Huang, Kerui; Miao, T.; Sagona, Antonia P.; Nezis, Ioannis P.; Bodmer, Rolf; Ocorr, Karen; Bai, Hua

doi:10.1080/15548627.2019.1704117

Cited by 62 publications

(43 citation statements)

References 91 publications

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“…The autophagic, apoptotic, and necrotic cell death pathways play important roles not only in skeletal muscle but also in cardiac tissues [37][38][39]. Impaired autophagy can lead to the premature death of cardiomyopathy and myocardium [40]. Furthermore, these cell death pathways contribute to myocardial function and sudden cardiac death, including ventricular arrhythmias and ventricular fibrillation.…”

Section: Discussionmentioning

confidence: 99%

The Autophagy Regulatory Molecule CSRP3 Interacts with LC3 and Protects Against Muscular Dystrophy

Cui

Han

Tang

et al. 2020

IJMS

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CSRP3/MLP (cysteine-rich protein 3/muscle Lim protein), a member of the cysteine-rich protein family, is a muscle-specific LIM-only factor specifically expressed in skeletal muscle. CSRP3 is critical in maintaining the structure and function of normal muscle. To investigate the mechanism of disease in CSRP3 myopathy, we performed siRNA-mediated CSRP3 knockdown in chicken primary myoblasts. CSRP3 silencing resulted in the down-regulation of the expression of myogenic genes and the up-regulation of atrophy-related gene expressions. We found that CSRP3 interacted with LC3 protein to promote the formation of autophagosomes during autophagy. CSRP3-silencing impaired myoblast autophagy, as evidenced by inhibited autophagy-related ATG5 and ATG7 mRNA expression levels, and inhibited LC3II and Beclin-1 protein accumulation. In addition, impaired autophagy in CSRP3-silenced cells resulted in increased sensitivity to apoptosis cell death. CSRP3-silenced cells also showed increased caspase-3 and caspase-9 cleavage. Moreover, apoptosis induced by CSRP3 silencing was alleviated after autophagy activation. Together, these results indicate that CSRP3 promotes the correct formation of autophagosomes through its interaction with LC3 protein, which has an important role in skeletal muscle remodeling and maintenance.

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Section: Discussionmentioning

confidence: 99%

The Autophagy Regulatory Molecule CSRP3 Interacts with LC3 and Protects Against Muscular Dystrophy

Cui

Han

Tang

et al. 2020

IJMS

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“…[74] Chang et al [75], recently delineated the role of TGFB-INHB/activin signaling in the regulation of autophagy and age-related cardiac dysfunction in Drosophila melanogaster (D. melanogaster). Specifically, cardiac specific knockdown of TGFB-INHB/activin-like protein daw (Dawdle, an activin ligand) activated D. melanogaster mTOR complex 2 (mtorc2) signaling, promoted autophagic flux, and preserved cardiac contractility and cardiac output in old flies [75]. In addition to TGFB, inflammation has been directly involved in the suppression of cardiac autophagy with age.…”

Section: Autophagy Suppression In Cardiac Agingmentioning

confidence: 99%

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Ghosh

Vinod

Symons

et al. 2020

Cells

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Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age.

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“…One of the critical tissues that require TGF-β/activin signaling for larval adaptation is muscle (Watanabe et al, 2019). In addition to these studies on the larval responses in gene expression and metabolism, how Daw-initiated TGF-β/activin signaling regulates functions of adult tissues and influences life span has been investigated on standard laboratory foods (Bai, Kang, Hernandez, & Tatar, 2013;Chang et al, 2019;Langerak et al, 2018); and intriguingly, adult muscles also depend on TGF-β/activin signaling to control the 26S proteasome level and realize normal life span (Langerak et al, 2018). Confusingly, however, two studies report opposing effects of whole-body knockdown of daw on life span (Bai et al, 2013;Langerak et al, 2018).…”

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confidence: 99%

Divergence of Drosophila species: Longevity and reproduction under different nutrient balances

et al. 2020

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How nutrition impacts growth, reproduction and longevity is complex because relationships between these life events are difficult to disentangle. As a first step in sorting out these processes, we carried out a comparative analysis of related species of Drosophila with distinct feeding habits. In particular, we examined life spans and egg laying of two generalists and three specialists on diets with distinct protein‐to‐carbohydrate ratios. In contrast to the generalist D. melanogaster, adult males of two specialists, D. sechellia and D. elegans, lived longer on a protein‐rich diet. These results and our previous studies collectively show that the diet to which larvae of each specialist species have adapted ensures a longer life span of adult males of that same species. We also found a species‐specific sexual dimorphism of life span in the above two specialists regardless of the diets, which was in sharp contrast to D. melanogaster. In D. melanogaster, males lived longer than females, whereas females of D. sechellia and D. elegans were longer‐lived than males, and those specialist females were exceedingly low in egg production, relative to the other species. We discuss our findings from perspectives of mechanisms, including a possible contribution of egg production to life span.

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

Cited by 62 publications

References 91 publications

The Autophagy Regulatory Molecule CSRP3 Interacts with LC3 and Protects Against Muscular Dystrophy

The Autophagy Regulatory Molecule CSRP3 Interacts with LC3 and Protects Against Muscular Dystrophy

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Divergence of Drosophila species: Longevity and reproduction under different nutrient balances

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