Restoration of SERCA ATPase as an Intervention to Muscle Impairment Associated with Oxidative Stress

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Disrupted intracellular calcium homeostasis is associated with various chronic muscle pathologies including sarcopenia. In support of this, the activity of SERCA, the Sarcoplasmic Reticulum (SR) Ca+2‐ATPase, a membrane enzyme that returns calcium to the SR lumen following muscle contraction, is reduced 14% in muscle of old wild type mice. Here we report a 27% decrease in SERCA activity in gastrocnemius muscle from mice lacking the superoxide scavenger CuZnSod (Sod1−/− mice), a mouse model of elevated oxidative stress and accelerated sarcopenia. The mechanism coupling reduced SERCA function with muscle impairment is not known. We hypothesize that restoring SERCA function will attenuate loss of muscle mass and function in the Sod1−/− mice. To test this, 2 month old Sod1−/− mice were treated for 7 weeks with CDN1163, a novel allosteric SERCA activator that acts directly to increase SERCA ATPase activity (50 mg/kg, IP, 3 times per week). Treatment with CDN1163 increased gastrocnemius muscle mass by 8% in CDN1163‐treated versus untreated Sod1−/− mice. In addition, the 22% reduction in specific force measured in untreated Sod1−/− versus age‐matched wild type mice was completely restored by 7 weeks of CDN1163 treatment. CDN1163 also reduced the oxidative damage measured as F2‐isoprostanes in muscle tissues by 50% compared to untreated Sod1−/− mice. Collectively our findings suggest that reduced function of the SERCA pump contributes to muscle atrophy and reduced force generation in the Sod1−/− mice and the pharmacological stabilization of SERCA with CDN1163 may be a powerful tool to counter age‐ and oxidative stress‐associated muscle impairment.Support or Funding InformationThis research was conducted while Dr. Rizwan Qaisar was a Diamond/AFAR award recipient and by a P01 grant (AG051442) to Dr. Holly Van Remmen.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.