Abstract
Introduction Reactive oxygen species (ROS) and free radicals are byproducts of oxidative metabolism that cause cellular damage and are implicated in the pathogenesis of age-related diseases. Mitochondria are the main cellular sites of ROS production. Recent studies reported a positive correlation between mitochondria dysfunction and age-associated disk cellular senescence and apoptosis. Hence, we hypothesize that reducing mitochondria-generated ROS would slow the onset of age-related intervertebral disk degeneration (IDD). We tested this hypothesis by chronically treating the Errc1-/D mouse model of accelerated aging with XJB-5-131, a mitochondria-targeted free radical scavenger previously demonstrated to be therapeutic in rodent models of hemorrhagic shock and sepsis. Materials and Methods Pairs of 5-week-old siblings of Ercc1-/▵ mice were treated with XJB-5-131 or oil carrier control (intraperitoneal injections, 2 mg/Kg, 3×/week, 15 weeks). Total proteoglycan content (safranin-O histology, DMMB assay) and synthesis (35S-sulfate incorporation) were measured. Transmission electron microscopy (TEM) was performed to assess disk mitochondria number and morphology in Ercc1-/▵ mice and wild-type littermates. Results TEM showed greater mitochondrial death in discs of Ercc1-/▵ mice compared to their wild-type littermates. Compared to oil-treated Ercc1-/▵ controls, disks from XJB-5-131 treated Ercc1-/▵mice showed greater (1.3×) proteoglycan matrix content and higher (1.9×) rate of proteoglycan synthesis. Conclusion Errc1-/Dmouse model of a human progeria had previously established as an accurate model of spine aging. Treatment of Errc1-/Dmice with a mitochondria-targeted ROS scavenger decreased disk proteoglycan loss. This result is consistent with our in vitro studies which showed XJB-5-131 is able to rescue reduced proteoglycan synthesis mediated by oxidative stress in human disk cells grown at high oxygen (20 vs. 5% oxygen). The findings in this study suggest that oxidative damage originating from mitochondria dysfunction plays an important role in disk health. The mitochondrial-targeted ROS free radical scavenger XJB-5-131 is potentially therapeutic in delaying the onset of age-related IDD. I confirm having declared any potential conflict of interest for all authors listed on this abstract Yes Disclosure of Interest None declared
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