Senolytics do not prevent muscle loss in Sod1 knockout mice

The accumulation of senescent cells is a hallmark of aging and age-related disease. Cellular senescence is a state of cell cycle arrest resulting, in part, from metabolic stress and reactive oxygen species (ROS) production. The importance of senescent cells in sarcopenia is underexplored with limited data for or against their contribution to the age-related loss of muscle mass and function. Oxidative stress is an imbalance between ROS production and neutralization. Mice with a knock-out of the endogenous antioxidant superoxide dismutase 1 (Sod1KO) have high levels of oxidative stress and a phenotype resembling accelerated frailty. Because of this association of oxidative stress and cellular senescence, we reasoned that Sod1KO mice would have a high senescence burden. Recently, the senolytic treatment of dasatinib and quercertin (DQ) in Sod1KO mice eliminated senescent cells and restored markers of liver health. Therefore, we hypothesized that reduction of senescent cells with DQ could prevent sarcopenia in Sod1KO mice. To test this hypothesis, we treated wildtype (WT) and Sod1KO mice with DQ or vehicle (Veh) from 6 months of age, the age at which the Sod1KO mice showed first signs of sarcopenia. Sod1KO mice had reduced muscle mass compared to WT mice, however, there was no effect of DQ treatment. In contrast, after 7 months of DQ treatment, the specific force generated by the extensor digitorum longus muscle in Sod1KO mice was greater than untreated by ~11% (Sod1KO-Veh 14.542 ± 0.550 N/cm 2 ; Sod1KO-DQ 16.212 ± 1.464 N/cm 2 , p=0.013), although there were no differences between Veh and DQ in maximum force. There was a main effect of genotype in fragmentation of the neuromuscular junction in Sod1KO, regardless of DQ treatment (WT-Veh 0.87 ± 1.52% vs Sod1KO-Veh 77.10 ± 2.09&%, p <0.001; WT-DQ 0.0 ± 0.0% vs Sod1KO-DQ 70.5 ± 18.1%, p <0.001). We also observed a genotype effect in protein turnover analysis, as Sod1KO mice had higher mitochondrial and myofibrillar protein synthesis rates than WT mice, while there was no effect of DQ treatment. There was a trend for greater maximally stimulated complex I respiration in muscle mitochondria from Sod1KO-DQ mice compared to Sod1KO-Veh mice (97.32 ± 29.47 vs 61.78 ± 33.89 pmol/(s·mg), p=0.065, respectively). However, there were no effects of genotype or treatment in maximally stimulated complex I+II and complex II respiration, as well as hydroperoxide generation among groups. Our study suggests that DQ senolytic treatment does not prevent oxidative stress-induced sarcopenia in Sod1KO mice. P01AG051442, 1 IK6 BX005234, 1 IK2 BX005620-01A1 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.