Nrf2 Deficiency Promotes Apoptosis and Impairs Pax7/MyoD Lineage in Aging Skeletal Muscle Sankarnarayanan Kannan1, Christopher J Davidson2, Naser Abu-Rmaileh2, Russell Richardson3, Aldrin V Gomes4, John R Hoidal5, and Rajasekaran Namakkal Soorappan2 1M.D. Anderson Cancer Center, United States, 2University of Utah, United States, 3University of Utah, United States, 4University of California, Davis, United States, 5University of Utah, United States Skeletal muscle (SM) redox homoeostasis is transcriptionally regulated by nuclear erythroid-2-p45-related factor-2 (Nrf2). We recently demonstrated that age-associated stress impairs Nrf2-ARE transcriptional signaling. Here, we hypothesize that age-dependent decline or genetic ablation of Nrf2 leads to accelerated apoptosis and SM degeneration. Under basal-physiological conditions, disruption of Nrf2 significantly down regulates antioxidants and cause oxidative stress. Surprisingly, Nrf2-/- mice had enhanced antioxidant capacity identical to wild-type (WT) upon acute exercise stress (AES), suggesting activation of Nrf2 independent mechanisms (i.e. PGC1Analysis of pro-survival pathways under the basal state reveal decreased Akt levels, while pp53, a repressor of Akt, was increased in Nrf2-/- versus WT mice. Upon AES, Akt and p-Akt levels were significantly (p<0.001) increased (>10 fold) along with profound down regulation of pp53 (p<0.01) in Nrf2-/- versus WT SM, indicating the onset of pro-survival mechanisms to compensate the loss of Nrf2 signaling. However, we found decreased stem cell population (Pax7) along with profound activation of ubiquitin and apoptotic pathways in Nrf2-/- versus WT mice on AES, suggesting that compensatory pro-survival mechanisms failed to overcome the cell death and degeneration in SM. in an age-associated oxidative stress condition, ablation of Nrf2 results in induction of apoptosis and impaired muscle regeneration.

doi: 10.1016/j.freeradbiomed.2013.10.686

doi: 10.1016/j.freeradbiomed.2013.10.687