Nrf2 augments skeletal muscle regeneration after ischaemia–reperfusion injury

Abstract

Skeletal muscles harbour a resident population of stem cells, termed satellite cells (SCs). After trauma, SCs leave their quiescent state to enter the cell cycle and undergo multiple rounds of proliferation, a process regulated by MyoD. To initiate differentiation, fusion and maturation to new skeletal muscle fibres, SCs up-regulate myogenin. However, the regulation of these myogenic factors is not fully understood. In this study we demonstrate that Nrf2, a major regulator of oxidative stress defence, plays a role in the expression of these myogenic factors. In both promoter studies with myoblasts and a mouse model of muscle injury in Nrf2-deficient mice, we show that Nrf2 prolongs SC proliferation by up-regulating MyoD and suppresses SC differentiation by down-regulating myogenin. Moreover, we show that IL-6 and HGF, both factors that facilitate SC activation, induce Nrf2 activity in myoblasts. Thus, Nrf2 activity promotes muscle regeneration by modulating SC proliferation and differentiation and thereby provides implications for tissue regeneration.

Redox Control of Skeletal Muscle Regeneration

“…CBR1 inhibition is associated with an increase of ROS production, and with impaired differentiation and skeletal muscle regeneration in vivo (190). Consistently, skeletal muscle regeneration is strongly delayed in Nrf2-deficient animals, where alteration in the time course of myogenesis is observed and has been attributed to an alteration of MuSC proliferation/differentiation balance (4,304).…”

“…Higher levels of GSH are found in type I muscle fibers, which have an oxidative/aerobic metabolism, as compared with type II fibers, which rely mainly on a glycolytic/anaerobic metabolism (185). 4. Family of thioredoxins.…”

Global deletion ofBCATmincreases expression of skeletal muscle genes associated with protein turnover

“…FPKM values for myosin heavy chain 4 (Mhy4), which is the most abundant myosin type in rodent gastrocnemius associated with the fastest most glycolytic fibers (IIb), was also decreased. 2 Looking at other sarcomeric components, BCATm KOs expressed higher amounts of genes encoding slower fiber (I) types of troponin C and myosin binding protein C (Tnnc1, Mybpc1), whereas the faster twitch fiber types (Tnnc2, Mybpc2) were decreased ( Table 4). The Mb gene encoding the O 2 -carrying protein, myoglobin, associated with more oxidative fiber types, was 2 During this part of our bioinformatics evaluation, it was noticed that Myh4, normally a major gene and protein component in muscle, had 0 FPKM values for several animals.…”

Dietary vitamin B6 modulates the gene expression of myokines, Nrf2-related factors, myogenin and HSP60 in the skeletal muscle of rats

“…Nrf2/ARE signalling is activated by acute exercise stress in the myocardium (14). Several previous studies have suggested that the role of Nrf2 goes beyond antioxidant mechanisms (15,16). Al-Sawaf et al (16) reported that Nrf2 regulated myogenic regulatory factor (Mrf) expression and that Nrf2-knockout retarded skeletal muscle regeneration after injury.…”

“…Several previous studies have suggested that the role of Nrf2 goes beyond antioxidant mechanisms (15,16). Al-Sawaf et al (16) reported that Nrf2 regulated myogenic regulatory factor (Mrf) expression and that Nrf2-knockout retarded skeletal muscle regeneration after injury. Heat shock proteins (HSPs) have also been reported to have a cytoprotective role in skeletal muscles (17).…”