Intervertebral disc (IVD) degeneration is a complicated process that involves both age-related change and tissue damage caused by multiple stresses. In a degenerative IVD, cellular senescence accumulates and is associated with reduced proliferation, compromised self-repair, increased inflammatory response, and enhanced catabolic metabolism. In this review, we decipher the senescence mechanism of IVD degeneration (IVDD) by interpreting how aging coordinates with age-related, microenvironment-derived stresses in promoting disc cell senescence and accelerating IVDD. After chronic and prolonged replication, cell senescence may occur as a natural part of the disc aging process, but can potentially be accelerated by growth factor deficiency, oxidative accumulation, and inflammatory irritation. While acute disc injury, excessive mechanical overloading, diabetes, and chronic tobacco smoking contribute to the amplification of senescence-inducing stresses, the avascular nature of IVD impairs the immune-clearance of the senescent disc cells, which accumulate in cell clusters, demonstrate inflammatory and catabolic phenotypes, deteriorate disc microenvironment, and accelerate IVDD. Anti-senescence strategies, including telomerase transduction, supply of growth factors, and blocking cell cycle inhibitors, have been shown to be feasible in rescuing disc cells from early senescence, but their efficiency for disc regeneration requires more in vivo validations. Guidelines dedicated to avoiding or alleviating senescence-inducing stresses might decelerate cellular senescence and benefit patients with IVD degenerative diseases.

Aim: Imbalanced mitochondrial dynamics including suppressed mitochondrial fusion has been observed in diabetic hearts. However, it is still unknown whether mitochondrial fusion promoter is an effective protection to diabetic hearts. This study was designed to explore the efficacy of mitochondrial fusion promoter on diabetic cardiomyopathy (DCM). Methods: Male Sprague-Dawley rats were injected with streptozotocin (STZ, 65 mg/kg/d) intraperitoneally to induce diabetes. Seven weeks after vehicle or STZ injection, control or diabetic rats were treated with the vehicle or a mitochondrial fusion promoter-M1 (2 mg/kg/d) intraperitoneally for 6 weeks. Moreover, M1 was administrated to the primary cardiomyocytes cultured in normal glucose medium (NG, 5.5 mmol/L) or high glucose (HG, 33 mnol/L). Results: Administration of M1 significantly promoted mitochondrial fusion and attenuated the reduction in optic atrophy 1 (Opa1) expression in diabetic hearts. Importantly, M1 treatment attenuated oxidative stress, improved mitochondrial function and alleviated DCM in diabetic rats. In HG-treated cardiomyocytes, M1 treatment consistently increased the expression of Opa1, promoted mitochondrial fusion, enhanced mitochondrial respiratory capacity and reduced mitochondria-derived superoxide production, all of which were blunted by Opa1 siRNA knockdown. In addition, selective upregulation of Opa1 alone can also promote mitochondrial fusion, improve mitochondrial function and inhibit mitochondria-derived superoxide production in HG-cultured cardiomyocytes. Conclusion: Our findings show for the first time that mitochondrial fusion promoter M1 effectively balances mitochondrial dynamics and protects against diabetic cardiomyopathy (DCM) via an Opa1-dependent way, suggesting that promoting mitochondrial fusion might be a potential therapeutic strategy for DCM. K E Y W O R D Sdiabetes, diabetic cardiomyopathy, mitochondrial fusion, Opa1, oxidative stress 2 of 14 | DING et al.

Intervertebral disc (IVD) degeneration results in segmental instability and irritates neural compressive symptoms, such as low back pain and motor deficiency. The transplanting of stem cell into degenerative discs has attracted increasing clinical attention, as a new and proven approach to alleviating disc degeneration and to relieving discogenic pains. Aside from supplementation with stem cells, the IVD itself already contains a pool of stem and progenitor cells. Since the resident disc stem cells are incapable of reversing the pathologic changes that occur during aging and disc degeneration, it has been debated as to whether transplanted stem cells are capable of providing an efficient and durable therapeutic effect, even though there have been positive outcomes in both animal models and in clinical trials. This review aims to decipher the interactions between the stem cell and the disc microenvironment. Within their new niches in the IVD, the exogenous stem cell shows metabolic adaptation to the low-glucose supply, hypoxia, and compressive loadings, but demonstrates little tolerance to the disc-like acidity and hypertonicity. Similarly, the survival of endogenous stem cells is threatened as well by the harsh disc microenvironment, which may exhaust the stem cell resources and restrict the self-repair capacity of a degenerating IVD. To eliminate the intrinsic obstacles within the stressful disc niches, stem cells should be delivered with an injectable scaffold that provides both survival and mechanical support. Quick healing or concretion of the injection injuries, which minimizes stem cell leakage and disturbance to disc homeostasis, is of equal importance toward achieving efficient stem cell-based disc regeneration.