Null Mutation of gp91^phox Reduces Muscle Membrane Lysis During Muscle Inflammation in Mice

Abstract

Muscle inflammation is a common feature in muscle injury and disease. Recently, investigators have speculated that inflammatory cells may increase or decrease muscle damage following modified muscle use, although there are few experimental observations to confirm either possibility. In the present study, a null mutation of gp91phox in neutrophils prevented superoxide production in cytotoxicity assays in which muscle cells were targets, and prevented most neutrophil‐mediated cytolysis of muscle cells in comparison to wild‐type neutrophils in vitro. We further tested whether deficiency in superoxide production caused a decrease in muscle membrane damage in vivo during modified muscle use. Gp91phox null mutant mice and wild‐type mice were subjected to 10 days of muscle hindlimb unloading followed by reloading through return to normal locomotion, which induced muscle membrane lesions and muscle inflammation. Membrane lesions were quantified by measuring the presence of extracellular marker dye in reloaded soleus muscle fibres. There was a 90 % reduction in the number of fibres showing extensive membrane injury in gp91phox null mice compared to controls. Mutation of gp91phox did not change the concentration of neutrophils or macrophages in the reloaded muscle. Furthermore, muscle fibre growth during the reloading period was unaffected by the reduction in membrane injury. Together, these findings show that neutrophils can induce muscle membrane lysis through superoxide‐mediated events, and indicate that superoxide‐mediated membrane damage in vivo is not required for myeloid cell chemotaxis or muscle growth during muscle reloading.

Dystrophin-deficient cardiomyopathy in mouse: Expression of Nox4 and Lox are associated with fibrosis and altered functional parameters in the heart

“…In a study using Nox2 (gp91phox) deficient mice, a 90% reduction in the number of muscle fibers showing extensive membrane injury was found compared to controls. [52] However, increased Nox2 activity was not seen in cardiac tissue and there were not extensive inflammatory infiltrates seen in mdx myocardial tissue (Figure 3). Therefore, the fibrosis seen in the mdx heart does not appear related to significant inflammatory cellular infiltrates and Nox2 is likely more involved with skeletal muscle pathology than cardiac muscle.…”

L’ulcèrede Buruli

“…D'autres mécanismes qui font intervenir les cellules inflammatoires et le facteur pro-inflammatoire NF-B ont été envisagés pour expliquer l'installation de l'atrophie. En particulier, les macrophages et les neutrophiles provoquent la lyse des cellules musculaires respectivement par l'intermédiaire de NO (monoxyde d'azote) et du peroxyde [21]. Le facteur pro-inflammatoire NF-B activé en présence de M. ulcerans [22] est, quant à lui, capable d'entraîner la dégradation de la protéine MyoD [17,23] et l'activation des ubiquitines ligases musculaires atrogine-1 et MuRF-1 [24], conduisant respectivement à un déficit de la régénération et à une lyse des protéines musculaires (Figure 4).…”

Determinants of Disuse-Induced Skeletal Muscle Atrophy: Exercise and Nutrition Countermeasures to Prevent Protein Loss

“…In addition, most of the genes downregulated and several genes upregulated during unloading return to basal levels within a few hours of recovery (78). These effects result in relatively rapid recovery of the fiber cross-sectional area (135,138) and muscle mass (15,(136)(137)(138)(139)(140)(141).…”

“…But this is not an easy undertaking, particularly because landing is associated with a metabolic stress response (34) and reloading of atrophied muscles upon re-exposure to terrestrial gravity results in mechanical stress-induced structural lesions of myofibers (129,130), particularly sarcomere damage (131), which is responsible for the delayed-onset muscle soreness experienced by astronauts upon returning to Earth (19). Furthermore, reloaded muscles of animals have significantly increased hydroperoxide levels (132) and undergo inflammation and superoxide-mediated membrane damage (133)(134)(135). To our knowledge, however, few studies have focused on the effects of reload on muscular protein kinetics in either humans or animals.…”