Interleukin‐6 myokine signaling in skeletal muscle: a double‐edged sword?

Muñoz‐Cánoves, Pura; Schéele, Camilla; Pedersen, Bente Klarlund; Serrano, Antonio L.

doi:10.1111/febs.12338

Cited by 559 publications

(491 citation statements)

References 155 publications

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“…Inflammation is a common physiologic response to exercise and leads to increased muscle mass. 27 IL-6 knockout mice were shown to have an impaired hypertrophic response to overloading. 28 We previously reported that myogenesis response to muscle injury was blunted in IL-6 knockout mice, 29 which proved the positive effect of IL-6 on myogenesis.…”

Section: Discussionmentioning

confidence: 99%

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

Klein

Hassounah

et al. 2015

Journal of the American Society of Nephrology

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Effective therapeutic strategies to treat CKD-induced muscle atrophy are urgently needed. Lowfrequency electrical stimulation (LFES) may be effective in preventing muscle atrophy, because LFES is an acupuncture technique that mimics resistance exercise by inducing muscle contraction. To test this hypothesis, we treated 5/6-nephrectomized mice (CKD mice) and control mice with LFES for 15 days. LFES prevented soleus and extensor digitorum longus muscle weight loss and loss of hind-limb muscle grip in CKD mice. LFES countered the CKD-induced decline in the IGF-1 signaling pathway and led to increases in markers of protein synthesis and myogenesis and improvement in muscle protein metabolism. In control mice, we observed an acute response phase immediately after LFES, during which the expression of inflammatory cytokines (IFN-g and IL-6) increased. Expression of the M1 macrophage marker IL-1b also increased acutely, but expression of the M2 marker arginase-1 increased 2 days after initiation of LFES, paralleling the change in IGF-1. In muscle cross-sections of LFES-treated mice, arginase-1 colocalized with IGF-1. Additionally, expression of microRNA-1 and -206, which inhibits IGF-1 translation, decreased in the acute response phase after LFES and increased at a later phase. We conclude that LFES ameliorates CKDinduced skeletal muscle atrophy by upregulation of the IGF-1 signaling pathway, which improves protein metabolism and promotes myogenesis. The upregulation of IGF-1 may be mediated by decreased expression of microRNA-1 and -206 and/or activation of M2 macrophages.

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Section: Discussionmentioning

confidence: 99%

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

Klein

Hassounah

et al. 2015

Journal of the American Society of Nephrology

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“…Indirect effects of IL-6 on IGF-1 signaling have also been reported. Increased circulating levels of IL-6 are associated with significantly reduced serum IGF-1 levels and elevated expression of muscle SOCS3 mRNA [22]. These suggest the role of IL-6 as a negative regulator of IGF-1 signaling.…”

Section: Discussionmentioning

confidence: 87%

Anti-osteoporotic effect of Gengnian Jianshen decoction in rats

Wang¹,

Lu²,

Fu³

et al. 2017

Trop. J. Pharm Res

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Purpose: To investigate the therapeutic effect and mechanism of action of Gengnian Jianshen Decoction (GJD) on ovariectomy-induced osteoporosis in rats. Methods: Female Sprague-Dawley rats were randomly assigned to a sham-operated group (control), and five ovariectomy (OVX) sub-groups, that is, OVX with vehicle (OVX), OVX with Xianling Gubao capsule (positive control drug, 120 mg/kg/day), and OVX with GJD doses (70, 140, and 280 mg/kg/day). The treatments were given orally daily for 16 weeks (starting 4 weeks after the rats were subjected to ovariectomy. Bone mineral density (BMD) of the L4 vertebrae and right femur of each rat was estimated. Serum levels of estradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), as well as interleukin-6 (IL-6) and insulin-like growth factor 1(IGF-1) of rats in all the groups were determined using ELISA. Results:The results showed that GJD dose-dependently inhibited BMD reduction in L4 vertebrae and femur, and significantly increased serum E2, FSH and LH levels (p < 0.05)

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“…IL-6 can positively regulate regenerative myogenesis and skeletal muscle growth (28). However, understanding of the mechanisms of how the regulation of IL-6 expression is coupled to extracellular signals remains incomplete.…”

Section: Discussionmentioning

confidence: 99%

A Phosphoproteomic Screen Identifies a Guanine Nucleotide Exchange Factor for Rab3A Protein as a Mitogen-activated Protein (MAP) Kinase Phosphatase-5-regulated MAP Kinase Target in Interleukin 6 (IL-6) Secretion and Myogenesis

Lee

Min

et al. 2017

Journal of Biological Chemistry

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Edited by Henrik G. DohlmanThe mitogen-activated protein kinases (MAPKs) have been shown to regulate skeletal muscle function. Previously, we showed that MAPK phosphatase-5 (MKP-5) negatively regulates myogenesis and regeneration of skeletal muscle through inhibition of p38 MAPK and c-Jun N-terminal kinase (JNK). However, the identity and contribution of MKP-5-regulated MAPK targets in the control of skeletal muscle function and regenerative myogenesis have not been established. To identify MKP-5-regulated MAPK substrates in skeletal muscle, we performed a global differential phospho-MAPK substrate screen in regenerating skeletal muscles of wild type and MKP-5-deficient mice. We discovered a novel MKP-5-regulated MAPK substrate called guanine nucleotide exchange factor for Rab3A (GRAB) that was hyperphosphorylated on a phospho-MAPK motif in skeletal muscle of MKP-5-deficient mice. GRAB was found to be phosphorylated by JNK on serine 169. Myoblasts overexpressing a phosphorylation-defective mutant of GRAB containing a mutation at Ser-169 to Ala-169 (GRAB-S169A) inhibited the ability of C2C12 myoblasts to differentiate. We found that GRAB phosphorylation at Ser-169 was required for the secretion of the promyogenic cytokine interleukin 6 (IL-6). Consistent with this observation, MKP-5-deficient mice exhibited increased circulating IL-6 expression as compared with wild type mice. Collectively, these data demonstrate a novel mechanism whereby MKP-5-mediated regulation of JNK negatively regulates phosphorylation of GRAB, which subsequently controls secretion of IL-6. These data support the notion that MKP-5 serves as a negative regulator of MAPKdependent signaling of critical skeletal muscle signaling pathways. MAPK phosphatases (MKPs)2 are members of the dual specificity protein-tyrosine phosphatase family that specifically dephosphorylate the MAPKs (1). We have shown that the MKPs can both positively and negatively regulate myogenesis through coordinate MAPK dephosphorylation (2-5). In particular, we have shown that loss of MKP-5 expression in mice results in enhanced satellite cell proliferation and differentiation, which contribute to the increased capacity of skeletal muscle to regenerate (3). Furthermore, genetic ablation of MKP-5 in a model of dystrophic muscle disease abrogates the dystrophic phenotype, suggesting an important role for MKP-5 in skeletal muscle disease progression (3). Thus, understanding the signaling pathway(s) regulated by MKP-5 in skeletal muscle homeostasis might provide new insight into the mechanisms of both skeletal muscle growth and the progression of dystrophic muscle disease.The maintenance of skeletal muscle function is a dynamic process that requires the interplay between skeletal muscle and trophic factors. An imbalance in the equilibrium between the factors that positively and negatively regulate skeletal muscle function is associated with diseases such as atrophy, cancer cachexia, muscular dystrophies, and neuromuscular disorders. Skeletal muscle produces and secretes a variety ...

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Interleukin‐6 myokine signaling in skeletal muscle: a double‐edged sword?

Cited by 559 publications

References 155 publications

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

Anti-osteoporotic effect of Gengnian Jianshen decoction in rats

A Phosphoproteomic Screen Identifies a Guanine Nucleotide Exchange Factor for Rab3A Protein as a Mitogen-activated Protein (MAP) Kinase Phosphatase-5-regulated MAP Kinase Target in Interleukin 6 (IL-6) Secretion and Myogenesis

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