Anti-interleukin-6 receptor antibody (MR16-1) promotes muscle regeneration via modulation of gene expressions in infiltrated macrophages

Fujita, Ryo; Kawano, Fumimori; Ohira, Takashi; Nakai, Norihiro; Shibaguchi, Tsubasa; Nishimoto, Norihiro; Ohira, Yoshinobu

doi:10.1016/j.bbagen.2014.01.014

Cited by 29 publications

(21 citation statements)

References 43 publications

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“…Because IL6 plays a role not only in muscle wasting but also in regeneration following muscle injury and because we observed increased myogenin expression in C26‐bearing mice electroporated with a PAK1 expressing plasmid, we wondered whether the inhibition of group I Paks by the in vivo administration of its inhibitor IPA‐3 had any effect on muscle regeneration. Because muscle regeneration is hardly activated in physiological conditions, we treated hind limb muscles of C57BL/6 mice with CTX injections to induce muscle injury and to activate the muscle repair machinery.…”

Section: Resultsmentioning

confidence: 99%

Group I Paks support muscle regeneration and counteract cancer‐associated muscle atrophy

Perpetuini

Cecconi

Chiappa

et al. 2018

J cachexia sarcopenia muscle

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BackgroundSkeletal muscle is characterized by an efficient regeneration potential that is often impaired during myopathies. Understanding the molecular players involved in muscle homeostasis and regeneration could help to find new therapies against muscle degenerative disorders. Previous studies revealed that the Ser/Thr kinase p21 protein‐activated kinase 1 (Pak1) was specifically down‐regulated in the atrophying gastrocnemius of Yoshida hepatoma‐bearing rats. In this study, we evaluated the role of group I Paks during cancer‐related atrophy and muscle regeneration.MethodsWe examined Pak1 expression levels in the mouse Tibialis Anterior muscles during cancer cachexia induced by grafting colon adenocarcinoma C26 cells and in vitro by dexamethasone treatment. We investigated whether the overexpression of Pak1 counteracts muscle wasting in C26‐bearing mice and in vitro also during interleukin‐6 (IL6)‐induced or dexamethasone‐induced C2C12 atrophy. Moreover, we analysed the involvement of group I Paks on myogenic differentiation in vivo and in vitro using the group I chemical inhibitor IPA‐3.ResultsWe found that Pak1 expression levels are reduced during cancer‐induced cachexia in the Tibialis Anterior muscles of colon adenocarcinoma C26‐bearing mice and in vitro during dexamethasone‐induced myotube atrophy. Electroporation of muscles of C26‐bearing mice with plasmids directing the synthesis of PAK1 preserves fiber size in cachectic muscles by restraining the expression of atrogin‐1 and MuRF1 and possibly by inducing myogenin expression. Consistently, the overexpression of PAK1 reduces the dexamethasone‐induced expression of MuRF1 in myotubes and increases the phospho‐FOXO3/FOXO3 ratio. Interestingly, the ectopic expression of PAK1 counteracts atrophy in vitro by restraining the IL6‐Stat3 signalling pathway measured in luciferase‐based assays and by reducing rates of protein degradation in atrophying myotubes exposed to IL6. On the other hand, we observed that the inhibition of group I Paks has no effect on myotube atrophy in vitro and is associated with impaired muscle regeneration in vivo and in vitro. In fact, we found that mice treated with the group I inhibitor IPA‐3 display a delayed recovery from cardiotoxin‐induced muscle injury. This is consistent with in vitro experiments showing that IPA‐3 impairs myogenin expression and myotube formation in vessel‐associated myogenic progenitors, C2C12 myoblasts, and satellite cells. Finally, we observed that IPA‐3 reduces p38α/β phosphorylation that is required to proceed through various stages of satellite cells differentiation: activation, asymmetric division, and ultimately myotube formation.ConclusionsOur data provide novel evidence that is consistent with group I Paks playing a central role in the regulation of muscle homeostasis, atrophy and myogenesis.

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Section: Resultsmentioning

confidence: 99%

Group I Paks support muscle regeneration and counteract cancer‐associated muscle atrophy

Perpetuini

Cecconi

Chiappa

et al. 2018

J cachexia sarcopenia muscle

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“…For bgalactosidase staining, muscle sections were fixed with 4% paraformaldehyde for 3 min and then incubated in 5-bromo-4-chloro-3-indolyl-b-D-galactopyranoside (X-gal) solution overnight at 37°C, rinsed 3 times with distilled water, briefly air dried, and then mounted with coverslips. Hematoxylin and eosin (H&E) staining was performed as described (30). For Oil-Red-O staining, Oil-Red-O stock solution [0.6 g Oil Red O (MilliporeSigma, St. Louis, MO, USA) in 100 ml isopropanol] was diluted with water (6:4) and sections incubated with the staining solution at 37°C for 20 min.…”

Section: Histologic Assessmentmentioning

confidence: 99%

Zmynd17 controls muscle mitochondrial quality and whole‐body metabolism

et al. 2018

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Muscle mitochondria are crucial for systemic metabolic function, yet their regulation remains unclear. The zinc finger MYND domain-containing protein 17 (Zmynd17) was recently identified as a muscle-specific gene in mammals. Here, we investigated the role of Zmynd17 in mice. We found Zmynd17 predominantly expressed in skeletal muscle, especially in fast glycolytic muscle. Genetic Zmynd17 inactivation led to morphologic and functional abnormalities in muscle mitochondria, resulting in decreased respiratory function. Metabolic stress induced by a high-fat diet upregulated Zmynd17 expression and further exacerbated muscle mitochondrial morphology in Zmynd17-deficient mice. Strikingly, Zmynd17 deficiency significantly aggravated metabolic stress-induced hepatic steatosis, glucose intolerance, and insulin resistance. Furthermore, middle-aged mice lacking Zmynd17 exhibited impaired aerobic exercise performance, glucose intolerance, and insulin resistance. Thus, our results indicate that Zmynd17 is a metabolic stress-inducible factor that maintains muscle mitochondrial integrity, with its deficiency profoundly affecting whole-body glucose metabolism.-Fujita, R., Yoshioka, K., Seko, D., Suematsu, T., Mitsuhashi, S., Senoo, N., Miura, S., Nishino, I., Ono, Y. Zmynd17 controls muscle mitochondrial quality and whole-body metabolism.

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“…Another animal model study that manipulated pro‐inflammatory cytokines more directly also showed improved muscle regeneration: Fujita et al. () recently investigated the effect of an IL‐6 receptor antibody (MR16‐1) on skeletal muscle regeneration following cardiotoxin‐induced muscle damage. The authors demonstrated that intraperitoneal MR16 administration accelerated muscle regeneration and the antibody was primarily localized in macrophages in the damaged muscle.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil and monocyte responses to downhill running: Intracellular contents of MPO, IL‐6, IL‐10, pstat3, and SOCS3

Vyver

Engelbrecht

Smith

et al. 2015

Scandinavian Med Sci Sports

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High-intensity exercise results in immune activation. This study determined whether (a) there is concordance between serum MPO and neutrophil and/or monocyte intracellular MPO content; (b) peripheral blood mononuclear cells respond to inflammatory interleukins (ILs) by increasing intracellular signaling. Healthy male (n = 12) volunteers participated in high-intensity running (12 × 5 min, 10% decline, 15 km/h). Blood sample (pre, post, 4 h) analyses included serum concentrations of IL-1β, IL-1ra, IL-4, IL-6, IL-8, IL-10, matrix metalloprotease-9 (MMP-9) and creatine kinase (CK). Intracellular IL-6, IL-10, MPO and STAT3/SOCS3 signaling were assessed in mononuclear cells. CK (1573 ± 756 u/L), MMP-9 (101 ± 27 ng/mL), neutrophil (9.89 ± 0.76 × 10(9) cells/L) and monocyte counts (1 ± 0.08 × 10(9) cells/L) increased at 4 h. At 4 h serum (7.1 ± 1.3 ng/mL) and monocyte MPO (1.7-fold) increased, whereas neutrophil MPO decreased (0.8-fold). Intracellular monocyte IL-10 and IL-6 decreased by 15% and 20-30%, respectively, coinciding with elevations in serum IL-10 of 14.5 ± 4.7 pg/mL and IL-6 of 5.4 ± 2.9 pg/mL, suggesting immune cell cytokine release in response to exercise. Intracellular PBMC p-STAT3 to total STAT3 ratio increased from pre to 4 h. Circulating monocytes are responsive to increased serum IL-6 suggesting a negative feedback loop via STAT3 signaling.

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Anti-interleukin-6 receptor antibody (MR16-1) promotes muscle regeneration via modulation of gene expressions in infiltrated macrophages

Cited by 29 publications

References 43 publications

Group I Paks support muscle regeneration and counteract cancer‐associated muscle atrophy

Group I Paks support muscle regeneration and counteract cancer‐associated muscle atrophy

Zmynd17 controls muscle mitochondrial quality and whole‐body metabolism

Neutrophil and monocyte responses to downhill running: Intracellular contents of MPO, IL‐6, IL‐10, pstat3, and SOCS3

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