Targeted activation of Nrf2 prevents losses in leg muscle mass and strength during 2 weeks of immobilization in young adults

Introduction: Leg immobilization results in substantial losses in muscle mass and strength. Strategies aimed at minimizing these losses have proven largely ineffective. Elevated oxidative stress has been identified as a potential mechanism contributing to these losses. Therefore, we tested the hypothesis that PB125, an activator of Nrf2 (the master regulator of the endogenous antioxidant system), and MitoQ, a mitochondrial-targeted antioxidant, would decrease the deleterious effects of limb immobilization on muscle mass and strength. Methods: A double-blind, placebo-controlled trial was performed in a cohort of twenty young healthy adults (6M/14F, Age: 28±7 y; Height: 169±7 cm; Mass: 70±14 kg). Participants were randomized into either placebo (n=7), PB125 (n=6), or MitoQ (n=7). Supplementation and measures of physical activity using an accelerometer began 2 weeks prior to single leg immobilization and continued through 2 weeks of immobilization. Knee extensor muscle strength was tested before and after immobilization using isometric maximal voluntary contractions (MVC) and isokinetic contractions (120 and 60 degrees/s). Muscle mass was determined by MRI, and thigh lean muscle volume from image slices between the patellar tendon and gluteal muscle were assessed. Results: Physical activity, measured by steps per day, decreased by 55-65% during limb immobilization for all groups (p <0.05). Isometric muscle strength was significantly decreased following placebo (145±40 to 119±27 kg; p <0.05) and MitoQ (148±36 to 118±36 kg; p <0.05), but not PB125 (140±55 to 144±71 kg, p=0.7). Similarly, isokinetic muscle strength measured at 120 and 60 degrees/s was significantly decreased in placebo and MitoQ but preserved with PB125. Lean muscle volume in the immobilized limb significantly decreased by ~4% in placebo (p<0.05) and MitoQ (p<0.05) but was preserved with PB125 (p =0.55). Conclusions: Targeted activation of Nrf2 with PB125 preserved muscle mass and strength following 2 weeks of leg immobilization. In contrast, both placebo and MitoQ had no impact on immobilization-induced losses in muscle mass and strength. These findings provide novel evidence that targeting Nrf2 offsets the detrimental skeletal muscle effects of limb immobilization in young, healthy individuals. NIH-R01HL142603 and VA Merit-I01CX001999. This is the full abstract presented at the American Physiology Summit 2024 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.