The JAK/STAT Pathway in Skeletal Muscle Pathophysiology

Abstract

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is a key intracellular mediator of a variety of metabolically relevant hormones and cytokines, including the interleukin-6 (IL-6) family of cytokines. The JAK/STAT pathway transmits extracellular signals to the nucleus, leading to the transcription of genes involved in multiple biological activities. The JAK/STAT pathway has been reported to be required for the homeostasis of different tissues and organs. Indeed, when deregulated, it promotes the initiation and progression of pathological conditions, including cancer, obesity, diabetes, and other metabolic diseases. In skeletal muscle, activation of the JAK/STAT pathway by the IL-6 cytokines accounts for opposite effects: on the one hand, it promotes muscle hypertrophy, by increasing the proliferation of satellite cells; on the other hand, it contributes to muscle wasting. The expression of IL-6 and of key members of the JAK/STAT pathway is regulated at the epigenetic level through histone methylation and histone acetylation mechanisms. Thus, manipulation of the JAK/STAT signaling pathway by specific inhibitors and/or drugs that modulate epigenetics is a promising therapeutic intervention for the treatment of numerous diseases. We focus this review on the JAK/STAT pathway functions in striated muscle pathophysiology and the potential role of IL-6 as an effector of the cross talk between skeletal muscle and other organs.

Keywords: IL-6 cytokine; JAK/STAT pathway; epigenetics; organ cross talk; skeletal muscle.

Figure 1

Diagram showing the main paracrine and dichotomic autocrine functions of the IL-6/JAK/STAT3 pathway in the pathophysiology of skeletal muscle. Skeletal muscle physiological contraction induces IL-6 release (black arrows), with paracrine effects on other organ metabolism. Upon injury or in DMD, IL-6 is released (orange arrows) following the inflammatory response and IL-6/JAK/STAT pathway promotes muscle repair by activating pro-myogenic genes (such as MyoD) that allow MuSC differentiation and fusion into new or existing myofibers. In catabolic conditions, IL-6 levels are elevated (red arrows) and induce muscle size loss, by activation of different pro-atrophic pathways in myofibers. In neurogenic atrophy, FAPs activate the IL-6/JAK/STAT pathway. In response to acute exercise, IL-6 is highly produced (blue arrows) and IL-6/JAK/STAT pathway is activated, inducing pro-proliferation and pro-fusion genes that control contribution of MuSC to myofiber growth. In the box, the IL-6/JAK/STAT3 signaling model is shown. IL-6 binds the IL-6r-Gp130 receptor complex and activates the JAK tyrosine kinases. Once activated, JAK proteins dimerize, phosphorylate, and activate their primary substrates, the STAT proteins. Phosphorylated STAT proteins dimerize and translocate to the nucleus, where they activate different target protein-coding genes.

Figure 2

(A) DNA methylation and histone modifications are involved in epigenetic modulations of IL-6/JAK/STAT pathway members. They induce chromatin conformational transitions, altering accessibility of the transcriptional machinery (transcriptional active chromatin—blue arrow; transcriptional inactive chromatin – red arrow). DNA methylation is a process by which methyl groups are added to the cytosine of the DNA molecule and acts to repress gene transcription. Histone acetylation transfers acetyl groups to the histones and increases gene expression. Histone deacetylation removes acetyl groups from histones, allowing the histone to wrap more tightly the DNA and preventing transcription. Histone methylation adds methyl groups to the amino acids of the histones. Methylation of histones can either increase (i.e., H3K79, H3K4) or decrease (i.e. H3K9, H3K27) gene transcription. (B) Epigenetic modifications of IL-6/JAK/STAT pathway member genes that lead to gene repression (red) or gene activation (blue). (C) Epigenetic switches involving IL-6/JAK/STAT pathway members that lead to gene repression (red) or gene activation (blue) in tumorigenesis and development.