HOX-1 and COX-2: Two differentially regulated key mediators of skeletal myoblast tolerance under oxidative stress

Abstract

The exact physiological role of oxidative stress as a primary cause for skeletal muscle pathological conditions involving muscle degeneration remains elusive. Therefore, the present study was performed so as to decipher the signalling pathways orchestrating the potential cytoprotective role of heme oxygenase 1 (HOX-1) as well as cyclooxygenase 2 (COX-2) in skeletal myoblasts exposed to H(2)O(2). Cell treatment with H(2)O(2) (0.5 mM) resulted in a time- and dose-dependent response of HOX-1 and COX-2 mRNA and protein levels, with ERK1/2, p38-MAPK and MSK1 found to mediate these effects. Furthermore, Src and JNKs blockade attenuated COX-2 response. Collectively, these novel findings highlight for the first time HOX-1 and COX-2 fundamental contribution to skeletal myoblast tolerance under oxidative stress, since their inhibition significantly attenuated viability of skeletal myoblasts. The data also delineate the various effectors regulating HOX-1 and COX-2 expression, probably alleviating muscle degeneration in related disorders.

Altered mitogen‐activated protein kinase signaling in dystrophic (mdx) muscle

“…This is in accordance with previous studies which demonstrated that p38 promotes muscle cell death under a range of stressful circumstances 25, 33–36. However, there are also reports that substances that can protect myotubes from stress act, at least in part, by means of p38 activation37–39 suggesting that this MAP kinase pathway can, under some circumstances, also promote muscle cell survival. These discrepancies both in the literature, and between our data and previous studies, are likely to stem from a range of differences in experimental conditions such as using cells from different lines (immortalized vs. primary), at different stages in differentiation and under varied treatment regimes.…”

Verbascoside Elicits Its Beneficial Effects by Enhancing Mitochondrial Spare Respiratory Capacity and the Nrf2/HO-1 Mediated Antioxidant System in a Murine Skeletal Muscle Cell Line

“…The protective role of verbascoside against oxidative stress presumably predisposes myoblasts to better regenerative performance. Indeed, the excessive production of ROS leads to apoptosis and inhibits muscle satellite cells' proliferation [50], whereas counteracting the oxidative stress-for example, by the genetic or pharmacological activation of HO-1-improves the viability and proliferation of myoblasts [51,52]. The increase in the SRC induced by verbascoside treatment might have similar beneficial repercussions, since the differentiation of myoblasts into mature myotubes is accompanied by a metabolic shift from glycolysis to oxidative phosphorylation and strictly depends on mitochondrial function and activity [53][54][55][56].…”

NRF2 Regulates Viability, Proliferation, Resistance to Oxidative Stress, and Differentiation of Murine Myoblasts and Muscle Satellite Cells

“…For example, glutathione peroxidase (GPX) protected C2C12 cells [ 38 ] and mSCs [ 39 ] against apoptosis, while its absence increased their susceptibility to oxidative stress and decreased proliferation [ 40 ]. Furthermore, HO-1 improved the survival of transplanted primary myoblasts [ 41 ] and its pharmacological inhibition reduced the viability of H 2 O 2 -treated myoblasts [ 42 ]. As NRF2 induces the expression of HO-1 [ 28 ], the impact of NRF2 on myoblasts, similar to that which we previously showed for HO-1, suggests that the effects exerted by NRF2 depend on HO-1.…”