Glutathione peroxidase 3, a new retinoid target gene, is crucial for human skeletal muscle precursor cell survival

Abstract

SummaryProtection of satellite cells from cytotoxic damages is crucial to ensure efficient adult skeletal muscle regeneration and to improve therapeutic efficacy of cell transplantation in degenerative skeletal muscle diseases. It is therefore important to identify and characterize molecules and their target genes that control the viability of muscle stem cells. Recently, we demonstrated that high aldehyde dehydrogenase activity is associated with increased viability of human myoblasts. In addition to its detoxifying activity, aldehyde dehydrogenase can also catalyze the irreversible oxidation of vitamin A to retinoic acid; therefore, we examined whether retinoic acid is important for myoblast viability. We showed that when exposed to oxidative stress induced by hydrogen peroxide, adherent human myoblasts entered apoptosis and lost their capacity for adhesion. Pre-treatment with retinoic acid reduced the cytotoxic damage ex vivo and enhanced myoblast survival in transplantation assays. The effects of retinoic acid were maintained in dystrophic myoblasts derived from facioscapulohumeral patients. RT-qPCR analysis of antioxidant gene expression revealed glutathione peroxidase 3 (Gpx3), a gene encoding an antioxidant enzyme, as a potential retinoic acid target gene in human myoblasts. Knockdown of Gpx3 using short interfering RNA induced elevation in reactive oxygen species and cell death. The anti-cytotoxic effects of retinoic acid were impaired in GPx3-inactivated myoblasts, which indicates that GPx3 regulates the antioxidative effects of retinoic acid. Therefore, retinoid status and GPx3 levels may have important implications for the viability of human muscle stem cells.

Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target

“…This result is consistent with previous studies, which found spironolactone prevents aldosterone‐induced inflammation and oxidative stress in cardiac cells; the authors speculated that it may be able to prevent oxidative stress that contributes to cardiac muscle wasting (40, 41). A previous study found that cells under oxidative stress up‐regulate the alcohol dehydrogenases ADH1B and ADH1C in order to convert retinol to retinoic acid, which has been shown to protect muscle cells (42). Retinoic acid in turn up‐regulates glutathione peroxidase GPX3 , which is a regulator of its antioxidant effects.…”

Epigallocatechin-3-gallate improves plantaris muscle recovery after disuse in aged rats

“…As there are data to suggest that at least in old Wistar rats, hypertrophy would be expected to precede nuclear acquisition (van der Meer et al, 2011a), the importance of oxidative stress to negatively affect differentiation of activated satellite cells and muscle regeneration (El et al, 2012) and thereby limit the ability to add new nuclei to the reloaded muscles as a mechanism to enhance hypertrophy (Wust et al, 2007) and improve recovery from muscle wasting requires additional investigation.…”

Are Antioxidants a Potential Therapy for FSHD? A Review of the Literature

“…El Haddad et al [77] reported that healthy and FSHD muscles pretreated with retinoic acid (RA; a metabolite of vitamin A) presented lower ROS levels and apoptosis than when exposed to H 2 O 2 overnight (both P < 0.05). Additionally, myoblast adhesion was restored by pretreatment with RA and associated with a higher IC50 (the H 2 O 2 concentration at which half of the cells adhere to the culture dish).…”