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Sodium Salicylate Inhibits NF-κB Mediated Inflammation Associated With Aging in Skeletal Muscle Precursors and Improves Muscle Regeneration
Indranil Sinha, MD1, Juhyun Oh, PhD2, Bernard T. Lee, MD, MBA3, Amy J. Wagers, PhD2.
1Brigham and Women's Hospital, Boston, MA, USA, 2Harvard Stem Cell Institute, Boston, MA, USA, 3Beth Israel Deaconess Medical Center, Boston, MA, USA.
Age-associated sarcopenia is the inability to maintain skeletal muscle mass in the setting of chronic skeletal muscle inflammation. This may arise from a decrease in the myogenic potential of skeletal muscle precursors (SMPs). This study investigates the role of the inflammatory mediator NF-κB in SMP aging.
Young (Y, 4 months) and old mice (O, 22-24 months) were utilized in this study. SMPs isolated from Y and O mice were subjected to assays including the ability to form myogenic colonies and differentiate into skeletal muscle. Skeletal muscle NF-κB activity was quantified by electrophoretic mobility shift assay (EMSA) and associated gene expression by RT-PCR. Muscle regeneration was quantified by counting newly formed myofibers following injury. To assess whether NF-κB inhibition could restore SMP function, Y and O mice were next treated for 6-8 weeks with sodium salicylate, and similar SMP and skeletal muscle regeneration studies were performed. Transgenic mice deficient in NF-κB signalling (MISR) were aged to assess SMP function in the absence of skeletal muscle NF-κB activity. In addition, transgenic mice with skeletal muscle specific over-expression of NF-κB mediated signalling were created to evaluate SMP function in an environment of increased NF-κB activity. Statistical significance was defined as results with p < 0.05.
SMP myogenic colony formation is decreased in O as compared to Y mice. EMSA confirmed there was an increase in hind-limb whole muscle NF-κB activity with aging. In SMPs isolated from O mice, multiple genes which are either direct targets or activators of the NF-κB pathway are transcriptionally upregulated as compared to Y controls. SMPs collected from sodium salicylate feed treated aged mice exhibited increase myogenic colony formation in comparison to O mice receiving a control feed. In addition, O mice treated with sodium salicylate display improved skeletal muscle regeneration on days 7 and 14 following injury (Figure 1). Skeletal muscle regeneration following dry ice injury is also improved in aged MISR mice as compared to age-matched littermate controls. In contrast, SC-IKK mice recover more poorly following muscle injury. These changes were partially abated by sodium salicylate administration.
Chronic inflammation, mediated by NF-κB, retards SMP myogenic potential and impairs skeletal muscle regeneration. Aged mice demonstrate poor recovery following skeletal muscle injury and high levels of NF-κB activity. MISR mice, which are deficient in skeletal muscle NF-κB activity, maintain SMP regenerative potential with aging. Conversely, SC-IKK mice, which over-express NF-κB activity, exhibit poor skeletal muscle regeneration. Sodium salicylate inhibits NF-kB activity and improves skeletal muscle regeneration in the setting of chronic inflammation. These findings suggest that inhibition of NF-κB can promote skeletal muscle rejuvenation and restore SMP myogenic potential.
Figure 1. Representative samples of skeletal muscle tissue sections taken 7 days following dry ice injury demonstrates robust repair in young mice, a decreased response in aged mice, and improved repair in aged mice having undergone treatment with sodium salicylate.
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