Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoD expression in aging skeletal muscle cells

Abstract

Skeletal muscle redox homoeostasis is transcriptionally regulated by nuclear erythroid-2-p45-related factor-2 (Nrf2). We recently demonstrated that age-associated stress impairs Nrf2-ARE (antioxidant response element) transcriptional signaling. Here, we hypothesize that age-dependent decline or genetic ablation of Nrf2 leads to accelerated apoptosis and skeletal muscle degeneration. Under basal-physiological conditions, disruption of Nrf2 significantly down regulates antioxidants and causes oxidative stress. Surprisingly, Nrf2-null mice had enhanced antioxidant capacity identical to wild-type (WT) upon acute endurance exercise stress (AEES), suggesting activation of Nrf2-independent mechanisms (i.e. PGC1α) against oxidative stress. Analysis of pro-survival pathways under the basal state reveals decreased Akt levels, while pp53, a repressor of Akt, was increased in Nrf2-null versus WT mice. Upon AEES, 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-null versus WT skeletal muscle, indicating the onset of pro-survival mechanisms to compensate the loss of Nrf2 signaling. However, we found a decreased stem cell population (Pax7) and MyoD expression (differentiation) along with profound activation of ubiquitin and apoptotic pathways in Nrf2- null versus WT mice upon AEES, suggesting that compensatory pro-survival mechanisms failed to overcome the programed cell death and degeneration in skeletal muscle. Further, the impaired regeneration was sustained in Nrf2-null vs. WT mice after 1 week of post-AEES recovery. In an age-associated oxidative stress condition, ablation of Nrf2 results in induction of apoptosis and impaired muscle regeneration.

Nrf2 mediates redox adaptations to exercise

“…A single bout of acute exercise in wild-type mice has been shown to increase Nrf2 gene expression [36], [40] as well as Nrf2 protein abundance in skeletal muscle [40] and Nrf2-dependent phase II enzymes [36], [41]. Two additional studies that measured the effects of exercise on Nrf2 signaling in mouse myocardium are essentially in agreement with the data from skeletal muscle [42], [43].…”

Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease

“…123). Indeed, apoptosis has been suggested to account for muscle atrophy in many diseases, such as skeletal muscle denervation, immobilization, chronic heart failure, skeletal muscle aging, and muscular dystrophy (Sandri et al, 1998;Libera et al, 1999;Vescovo et al, 2000;Sandri et al, 2001;Pollack et al, 2002;Dirks and Leeuwenburgh, 2002;Siu and Alway, 2005;Machida and Booth, 2005;Jejurikar et al, 2006;Chung and Ng, 2006;Siu and Alway, 2009;Wohlgemuth et al, 2010;Narasimhan et al, 2014). Skeletal muscle abnormalities in PD have been reported to include inflammatory myopathies (Gdynia et al, 2009).…”

“…Elevated levels of p53 and active caspase-3 have been reported in many muscular diseases, such as aging skeletal muscle and sarcopenia (Chung and Ng, 2006;Marzetti and Leeuwenburgh, 2006). Moreover, apoptosis has been reported to contribute to the muscle atrophy and loss in muscular diseases (Sandri et al, 1998;Libera et al, 1999;Vescovo et al, 2000;Sandri et al, 2001;Pollack et al, 2002;Dirks and Leeuwenburgh, 2002;Siu and Alway, 2005;Machida and Booth, 2005;Jejurikar et al, 2006;Chung and Ng, 2006;Siu and Alway, 2009;Wohlgemuth et al, 2010;Narasimhan et al, 2014).…”

Redox Control of Skeletal Muscle Regeneration

“…The antioxidant Nrf2 signaling is impaired in aging muscle (219). Of note, in Nrf2-deficient mice subjected to acute endurance exercise stress, an alteration in the expression of the MuSC markers Pax7 and MyoD is observed along with the activation of ubiquitin and apoptotic pathways (234).…”