Autophagy and mTOR signaling during intervertebral disc aging and degeneration

Abstract

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.

Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases

“…Consistent with this findings, it was suggested that the secretion of LC3II/I, Unc-51 like kinase 1 (Ulk-1), and Beclin-1 was significantly reduced with aging, while the expression of SQSTM1/p62 (sequestosome 1) and osteocytic apoptosis were dramatically elevated, implying senile osteoporosis concomitant with bone loss might be attributed to weakening osteocytic autophagy, which is independent of apoptosis 124 ( Table 1). This also is in line with the result that autophagy might protect the skeleton against age-related bone loss, in part at least, through decreasing the activity of apoptosis, whereas, suppression of autophagy could result in the elevation of damaged mitochondria and oxidative stress product (e.g., ROS) [121][122][123]125 ( Table 1). It is intriguing that Beclin-1, an anti-apoptotic biomarker in autophagy, could be cleaved by caspases, thereby acquiring a new function and amplifying mitochondrion-mediated apoptosis due to the C-terminal fragment of Beclin-1 126,127 , implying a cross-talk mechanism between autophagy and apoptosis ( Fig.…”

“…Accumulated evidence indicates that the autophagy pathway has a protective role in preserving the osteocytic vitality under the state of low oxygen pressure (PO2 ) or low-dose GCs therapy 80 , 81 , 121 . In this line, it was demonstrated that autophagy, as an anti-apoptotic factor, could be negatively mediated via the mTOR pathway with aging, thereby leading to cell senescence and apoptosis 122 . Likewise, bone turnover was reduced and p66 shc phosphorylation was increased in L6 vertebrae of Dmp1-Cre; Atg7f/f mice, suggesting inhibition of osteocytic autophagy could generate the evidence of bone aging in many ways 123 .…”

The Factors and Pathways Regulating the Activation of Mammalian Primordial Follicles in vivo

“…The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates cell growth, metabolism, survival, and migration, which modulate processes such as protein synthesis, ribosome biogenesis, and autophagy (Laplante and Sabatini, 2012;Yurube et al, 2020). PI3K/Akt not only localizes FOXO3 in the cytoplasm but also could activate mTOR signal.…”

The Role of Hyaluronic Acid in Intervertebral Disc Regeneration

“…Transforming growth factor-beta (TGF-β) IVD [111] Mammalian target of rapamycin (mTOR) IVD [112] Wingless-related integration site (Wnt) AF, NP, end Plate (EP), growth plate (GP) [113][114][115][116][117][118] Nuclear factor-kappa beta (NF-κB) AF, NP, IVD [119][120][121][122][123][124][125] Nerve growth factor (NGF) AF, NP [126][127][128][129][130][131] Mitogen-activated protein kinase (MAPK) AF, NP [132][133][134][135][136][137][138] Notch signalling (NOTCH) AF, NP [139] Fibroblast growth factor (FGF) AF, NP [140,141] Interferon-alpha signalling canonical pathway (IFNα) AF [12,60] To assess the efficacy of collagen-I and HA injection in IVD repair, both including and excluding GF.…”