Skeletal muscle wasting and renewal: a pivotal role of myokine IL-6

Abstract

Adult skeletal tissue is composed of heterogeneous population of cells that constantly self-renew by means of a controlled process of activation and proliferation of tissue-resident stem cells named satellite cells. Many growth factors, cytokines and myokines produced by skeletal muscle cells play critical roles in local regulation of the inflammatory process and skeletal muscle regeneration during different pathological conditions. IL-6 is a pleiotropic cytokine released in large amount during infection, autoimmunity and cancer. Low levels of IL-6 can promote activation of satellite cells and myotube regeneration while chronically elevated production promote skeletal muscle wasting. These distinct effects may be explained by a crosstalk of the IL-6/IL-6 receptor and gp130 trans-signaling pathway that oppose to regenerative and anti-inflammatory of the classical IL-6 receptor signaling pathway. Here we discuss on potential therapeutic strategies using monoclonal antibodies to IL-6R for the treatment of skeletal muscle wasting and cachexia. We also highlight on the IL-6/JAK/STAT and FGF/p38αβ MAPK signaling pathways in satellite cell activation and the use of protein kinase inhibitors for tailoring and optimizing satellite cell proliferation during the skeletal muscle renewal. Future investigations on the roles of the IL-6 classical and trans-signaling pathways in both immune and non-immune cells in skeletal muscle tissue will provide new basis for therapeutic approaches to reverse atrophy and degeneration of skeletal muscles in cancer and inflammatory diseases.

Keywords: Anti-IL-6 receptor monoclonal antibodies; Cancer cachexia; Exercise; IL-6; IL-6/IL-6R/gp130 signaling pathway; Jak/STAT signaling; Satellite cells; Skeletal muscle.

Figures

Fig. 1

Immunohistochemical identification of satellite cells and myonuclei in human vastus lateralis muscle. Satellite cells are distinguished using co-staining for Pax7, laminin and DNA. Panels are images of a representative cross-section of skeletal muscle tissue stained for: Pax7 (a), myonuclei with Hoescht 33342 (b), laminin (c) and the merge image (d). Adapted from Brooks et al.

Fig. 2

IL-6 classical and trans-signaling pathways. a IL-6 binds to cells that express both the membrane bound IL-6R gp130 and trigger the activation of the JAK/STAT signaling pathway. This type of signaling is called classical signaling. b In cells that express only gp130 but not IL-6R, IL-6 binds to soluble IL-6R (sIL-6R) and the complex in turn bind to gp130 to trigger the activation of intracellular signaling. This type of signaling is called trans-signaling. The sIL-6R is released by proteolytic cleavage of the IL-6R membrane bound precursor by the metalloproteases ADAM10 and 17. A natural form of gp130 is able to bind to the sIL-6R bound to IL-6 with comparable affinity and mediates inhibition of IL-6 trans-signaling

Fig. 3

Skeletal muscle morphological alterations in cancer cachexia revealed by confocal (a–d) and transmitted electron (e, f) microscopic examination of a cross section of soleus muscle from mouse bearing B16 melanoma and severe cachexia as compared to normal soleus obtained from control C57BL/6 mouse. Myocyte apoptotic cell death is characterized by DNA fragmentation and deposition of chromatin masses around nuclear membrane. In a, a representative image illustrating the normal flattened nuclei located in parallel with skeletal muscle fibers in the periphery of normal myotube. In b, the image shows irregular nucleus with visible clumping of nuclear chromatin confirming cell death by apoptosis. In c, the micrograph shows the myosin banding displaying regular cross-striations and intense fluorescence. In d, illustrates myosin appearance in cachectic skeletal muscle fiber. The weak fluorescence intensity is reflecting breakdown of myofibril and tissue architecture. Nuclei were stained with propidium iodide and myosin pattern was revealed with monoclonal antibody to fast myosin skeletal heavy chain (lower panel). In e, the electron micrograph shows a nucleus with normal morphology (upper side) and a typical apoptotic nucleus with condensed chromatin fragments at its periphery (lower side). In f, the micrograph shows a portion of sarcolemma surrounded by mitochondria and vacuoles containing apoptotic bodies (autophagosome). The ubiquitin–proteasome and autophagy-lysosome pathways are the two major routes for protein and organelle degradation along skeletal muscle wasting

Fig. 4

Mediators and signaling pathways involved in the control of myotube degradation and repairing via satellite cell activation. a Schematic representation of muscle growth and muscle wasting pathways generated in the studies of gene expression patterns in skeletal muscle from cancer cachexia mice models. Genes with growth-promoting activity in skeletal muscle are shown in orange and genes involved muscle wasting in green and genes involved in satellite cell activation in blue. This set of genes is significantly up-regulated during food deprivation, diabetes, uremia, and cancer cachexia and target genes under the control of FoxO transcription factors in skeletal muscle wasting. b Quiescent satellite cells (white) activated by myokines and injury initiate symmetric and asymmetric divisions to produce activated satellite cells (green) and self-renewing satellite cell and myogenic stem cells (blue). After many rounds of division their progeny differentiate into myocytes and then myotubes. A different set of the transcription factors and membrane protein are expressed along each differentiation state of satellite cells. Some specific biomarkers are indicated in the panels inside the figure. Adapted from Bonetto et al. (2014) and Yin et al. (2013). IGF insulin-like growth factor; INSR, insulin receptor substrate 1; IGFR, insulin-like growth factor receptor; PI3K, phosphoinositide 3-kinase; GSK3, Glycogen synthase kinase 3; 4E-BP1, Eukaryotic translation initiation factor 4E binding protein 1; mTOR, mammalian target of rapamycin; p70S6K, serine/threonine kinase; Akt, Protein kinase B; FoxO, Forkhead box O transcription factors; IL-6, interleukin-6; LIF, leukemia inhibitory factor, TNF, tumor necrosis factor, IL-1, interleukin-1, TRAF, TNF receptor associated factor; NF-κB, factor nuclear kappa B; IKK, inhibitor of nuclear factor kappa-B kinase; MAPK, mitogen-activated protein kinase; JAK, janus kinase; STAT, Signal Transducer and Activator of Transcription; ERK, extracellular signal regulated kinase; ALK, activin receptor-like kinase, ACVR2B, activin receptor, SMAD, transcription factor; Atrogin, E3 ubiquitin ligases Muscle Atrophy Fbox (MAFbx); MURF1, Muscle Ring Finger 1, MHC, myosin heavy chain; MCK, muscle creatine kinase; SOCS, Suppressor of cytokine signaling; BCL2/adenovirus E1B 19 kDa protein-interacting protein 3

Fig. 5

Pharmacological approaches in pre-clinical and clinical trials for treating inflammatory diseases and muscle wasting in cancer cachexia. a Chemical and biological inhibitors of IL-6, b sIL-6R, c IL-6R, and d small molecule inhibitors of protein kinases, in the IL-6R downstream signaling pathways. The binding of IL-6 to IL-6R is inhibited by monoclonal antibodies sirukumab, clazakizumab and olokizumab. The interaction of IL-6R with gp130 is blocked by the monoclonal antibodies tocilizumab, sarilumab, ALD518 and siltuximab. FE999301 is a Fc-linked sgp130 recombinant protein that block the interaction of the complex formed by sgp130, soluble IL-6 and IL-6R that act as antagonist of interleukin-6 receptor trans-signaling responses. In box d are examples of small molecule inhibitors of p38α/β protein kinase activity with most highly selectivity and in box e are examples of phosphopeptide-based prodrugs targeting the SH2 domain of STAT3. SHIP1, SOCS and PIAS are natural negative regulators of JAK/STAT signaling pathways. Abbreviations: PIAS, the protein inhibitors of activated STATs, SOCS, Suppressor of Cytokine Signaling, NF-κB, factor nuclear kappa B, C/EBPβ, Enhancer Binding Protein Beta, AP-1, Activator Protein-1, ISRE, the IFN-stimulatory element, GAS, the IFN-γ-activation site, and TFs, transcription factors