Recombinant human SIRT1 protects against nutrient deprivation-induced mitochondrial apoptosis through autophagy induction in human intervertebral disc nucleus pulposus cells

Miyazaki, Shingo; Kakutani, Kenichiro; Yurube, Takashi; Maeno, Kazuo; Takada, Toru; Zhang, Zhongying; Kurakawa, Takuto; Terashima, Yoshiki; Ito, Masaaki; Ueha, Takeshi; Matsushita, Takehiko; Kuroda, Ryosuke; Kurosaka, Masahiro; Nishida, Kotaro

doi:10.1186/s13075-015-0763-6

Cited by 77 publications

(68 citation statements)

References 42 publications

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“…Serum and nutrient deprivation decreased rabbit disc AF cell proliferation and metabolic activity and increased autophagy, apoptosis, and senescence . Serum deprivation‐induced autophagy in disc cells is consistent with prior reports . Our findings support the understanding of disc cell fate and the monitoring of autophagic flux.…”

Section: Serum and Nutrient Deprivation In Rabbit Disc Cellssupporting

confidence: 91%

Autophagy and mTOR signaling during intervertebral disc aging and degeneration

et al. 2020

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Degenerative disc disease is a highly prevalent, global health problem that represents the primary cause of back pain and is associated with neurological disorders, including radiculopathy, myelopathy, and paralysis, resulting in worker disability and socioeconomic burdens. The intervertebral disc is the largest avascular organ in the body, and degeneration is suspected to be linked to nutritional deficiencies. Autophagy, the process through which cells self‐digest and recycle damaged components, is an important cell survival mechanism under stress conditions, especially nutrient deprivation. Autophagy is negatively controlled by the mammalian target of rapamycin (mTOR) signaling pathway. mTOR is a serine/threonine kinase that detects nutrient availability to trigger the activation of cell growth and protein synthesis pathways. Thus, resident disc cells may utilize autophagy and mTOR signaling to cope with harsh low‐nutrient conditions, such as low glucose, low oxygen, and low pH. We performed rabbit and human disc cell and tissue studies to elucidate the involvement and roles played by autophagy and mTOR signaling in the intervertebral disc. In vitro serum and nutrient deprivation studies resulted in decreased disc cell proliferation and metabolic activity and increased apoptosis and senescence, in addition to increased autophagy. The selective RNA interference‐mediated and pharmacological inhibition of mTOR complex 1 (mTORC1) was protective against inflammation‐induced disc cellular apoptosis, senescence, and extracellular matrix catabolism, through the induction of autophagy and the activation of the Akt‐signaling network. Although temsirolimus, a rapamycin derivative with improved water solubility, was the most effective mTORC1 inhibitor tested, dual mTOR inhibitors, capable of blocking multiple mTOR complexes, did not rescue disc cells. In vivo, high levels of mTOR‐signaling molecule expression and phosphorylation were observed in human intermediately degenerated discs and decreased with age. A mechanistic understanding of autophagy and mTOR signaling can provide a basis for the development of biological therapies to treat degenerative disc disease.

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Section: Serum and Nutrient Deprivation In Rabbit Disc Cellssupporting

confidence: 91%

Autophagy and mTOR signaling during intervertebral disc aging and degeneration

et al. 2020

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“…A more recent study showed that resveratrol, prevented cell apoptosis by enhancing LC3-II/I and Beclin-1 protein levels, eventually leading to augmented macroautophagy in human NP cells of the IVD [42••]. This study was supported by another report by Miyazaki and colleagues, showing that exogenous administration of rhSIRT1 under low nutrient conditions, promoted autophagy, and prevented apoptosis of human NP-cultured cells [43]. Resveratrol-activated SIRT1, resulted in deacetylated p65/RelA, and attenuated iNOS expression following IL1β-mediated inflammatory stimulation of chondrocytes [44••].…”

Section: Sirt1 Survival Effectsupporting

confidence: 72%

The Role of Sirtuins in Cartilage Homeostasis and Osteoarthritis

2016

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The past decade has witnessed many advances in the understanding of sirtuin biology and related regulatory circuits supporting the capacity of these proteins to serve as energy-sensing molecules that contribute to healthspan in various tissues, including articular cartilage. Hence, there has been a significant increase in new investigations that aim to elucidate the mechanisms of sirtuin function and their roles in cartilage biology, skeletal development, and pathologies such as osteoarthritis (OA), rheumatoid arthritis (RA), and intervertebral disc degeneration (IVD). The majority of the work carried out to date has focused on SIRT1, although SIRT6 has more recently become a focus of some investigations. In vivo work with transgenic mice has shown that Sirt1 and Sirt6 are essential for maintaining cartilage homeostasis and that the use of sirtuin-activating molecules such as resveratrol may have beneficial effects on cartilage anabolism. Current thinking is that SIRT1 exerts positive effects on cartilage by encouraging chondrocyte survival, especially under stress conditions, which may provide a mechanism supporting the use of sirtuin small-molecule activators (STACS) for future therapeutic interventions in OA and other degenerative pathologies of joints, especially those that involve articular cartilage.

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“…Ito et al demonstrated that resident disc cells utilize autophagy to cope with harsh, low-nutrient environments [49]. Miyazaki et al showed that SIRT1, as a potent treatment agent for human degenerative IVD disease, can protect against nutrient deprivation-induced mitochondrial apoptosis through autophagy induction in human NP cells [50]. In our study, we also confirmed that ER stress can induce autophagy in human cultured NP cells.…”

Section: Discussionsupporting

confidence: 78%

Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

et al. 2018

Cell Physiol Biochem

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Background/Aims: Intervertebral disc degeneration (IDD) is a pathological process that is the primary cause of low back pain and is potentially mediated by compromised stress defense. Sestrins (Sesn) promote cell survival under stress conditions and regulate AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling. Here, we investigated the expression of Sesn in normal and degraded nucleus pulposus (NP) cells and its potential roles during IDD pathogenesis. Methods: Sesn expression in normal and degraded NP cells was determined by quantitative polymerase chain reaction and immunoblotting and immunohistochemistry, respectively. Sesn function was investigated by using Sesn knockdown and overexpression techniques with analysis of extracellular matrix (ECM), cell apoptosis, autophagy, AMPK, and mTOR activation. Results: In human cultured NP cells, Sesn expression was significantly decreased in degraded NP cells at both the RNA and protein levels. The expression of Sesn1, 2, and 3 increased after stimulation by 2-deoxyglucose (2-DG), an endoplasmic reticulum stress inducer. 2-DG could also increase cell apoptosis, promote extracellular matrix (ECM) degradation, and positively regulate autophagy in NP cells. Sesn knockdown by small interfering RNA increased NP cell apoptosis and ECM degradation under basal culture conditions and in the presence of 2DG. Conversely, Sesn overexpression mediated by plasmid transfection repressed IDD by enhancing autophagy, which was associated with changes in mTOR but not AMPK activation. Conclusions: Sesn expression is suppressed in degraded NP cells. In addition, Sesn inhibits stress-induced cell apoptosis and ECM degradation by enhancing autophagy, which is modulated though mTOR activity. Suppression of Sesn might therefore represent an important cellular dysfunction mechanism in the process of IDD.

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Recombinant human SIRT1 protects against nutrient deprivation-induced mitochondrial apoptosis through autophagy induction in human intervertebral disc nucleus pulposus cells

Cited by 77 publications

References 42 publications

Autophagy and mTOR signaling during intervertebral disc aging and degeneration

Autophagy and mTOR signaling during intervertebral disc aging and degeneration

The Role of Sirtuins in Cartilage Homeostasis and Osteoarthritis

Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

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