Signal transducer and activator of transcription 3 signaling as a potential target to treat muscle wasting diseases

Sala, David; Sacco, Alessandra

doi:10.1097/mco.0000000000000273

Cited by 26 publications

(25 citation statements)

References 41 publications

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“…3b). Among them, the concurrent activation of STAT3 and IL6, which have been reported to be functionally interconnected 19–22 , stood out as the main activated pathway from both IPA (Fig. 2g and Suppl.…”

Section: Resultsmentioning

confidence: 92%

Denervation-activated STAT3–IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis

et al. 2018

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Fibro-adipogenic progenitors (FAPs) are typically activated in response to muscle injury, and establish functional interactions with inflammatory and muscle stem cells (MuSCs) to promote muscle repair. We found that denervation causes progressive accumulation of FAPs, without concomitant infiltration of macrophages and MuSC-mediated regeneration. Denervation-activated FAPs exhibited persistent STAT3 activation and secreted elevated levels of IL-6, which promoted muscle atrophy and fibrosis. FAPs with aberrant activation of STAT3-IL-6 signalling were also found in mouse models of spinal cord injury, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and in muscles of ALS patients. Inactivation of STAT3-IL-6 signalling in FAPs effectively countered muscle atrophy and fibrosis in mouse models of acute denervation and ALS (SOD mice). Activation of pathogenic FAPs following loss of integrity of neuromuscular junctions further illustrates the functional versatility of FAPs in response to homeostatic perturbations and suggests their potential contribution to the pathogenesis of neuromuscular diseases.

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Section: Resultsmentioning

confidence: 92%

Denervation-activated STAT3–IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis

et al. 2018

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“…They have similar amino acid sequences and play an independent regulation of cell signal transduction in human body. 42,43 Among them, STAT3 is an important signaling cascade component in STAT family and is widely involved in the response of a variety of cytokines. 44,45 Activation of STAT3 signal transduction pathway is closely related to cell proliferation, differentiation, apoptosis, angiogenesis, invasion, metastasis, and immune escape.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-125a-5p plays a role as a tumor suppressor in lung carcinoma cells by directly targeting STAT3

et al. 2017

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Increasing evidence supports that the dysregulation of microRNA expression plays an important role in the process of tumor occurrence and development. Studies have found that mir-125a-5p expression was downregulated in a variety of tumors, but the effects and mechanism of mir-125a-5p in lung cancer are still unclear. The aim of this study is to detect the expression of mir-125a-5p in lung cancer tissues and lung cancer cell lines and to explore the effects of mir-125a-5p on the biological characteristics of lung cancer cells; thus, this study aims to provide new methods and new strategies for the treatment of lung cancer. The result from quantitative reverse transcription polymerase chain reaction showed that the expression of miR-125a-5p was significantly lower in lung cancer tissues and lung cancer cell lines (95-D, A549, HCC827, and NCI-H1299) than that in normal tissue adjacent to lung cancer or normal human bronchial epithelial cells. In order to explore the function and mechanism of mir-125a-5p in lung cancer cells, miR-125a-5p mimic or mir-125a-5p inhibitor was transfected into A549 cells. Mir-125a-5p displayed an obvious upregulation in A549 cells transfected with miR-125a-5p and an obvious downregulation in A549 cells transfected with mir-125a-5p inhibitor compared to that in A549 cells transfected with control miRNA. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, BrdU staining, flow cytometry, and Transwell assay showed that the upregulation of miR-125a-5p could significantly decrease the cell viability, proliferation, and invasion of lung cancer cells and increase apoptosis of lung cancer cells. The downregulation of miR-125a-5p provided very contrasting results. Computational algorithms predicted that the STAT3 is a target of miR-125a-5p. Here, we validated that miR-125a-5p could directly bind to the 3'-untranslated region of STAT3, and miR-125a-5p overexpression could significantly inhibit the protein expression of STAT3. These results suggested that mir-125a-5p can regulate the expression of STAT3 in lung cancer cells. To further verify whether mir-125a-5p can play a biological role through regulating STAT3, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, flow cytometry, and Transwell analysis demonstrated that overexpression of STAT3 can reverse the cells' biological effects induced by mir-125a-5p overexpression. Mir-125a-5p downregulated in lung cancer tissue and cell lines can negatively regulate STAT3 protein expression. Taken together, mir-125a-5p inhibited the proliferation and invasion of lung cancer cells and facilitated lung cancer cell apoptosis through suppressing STAT3. Enhancing the expression of miR-125a-5p is expected to benefit the therapy for the patients with lung cancer.

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“…In the muscle microenvironment, a JAK/STAT pathway contribution in catabolic conditions can be considered in relation to its role in promoting the expansion of the satellite cell pool in vitro and in vivo , impairing differentiation and muscle repair (He et al., 2013; Muñoz-Cánoves et al., 2013; Price et al., 2014; Tierney et al., 2014; Sala and Sacco, 2016; Zhu et al., 2016). Other than activation of STAT3 in MuSCs, secreted and elevated IL-6 levels and persistent STAT3 activation were observed in atrophic conditions in the fibro/adipogenic progenitors (FAPs), a population of cells resident in skeletal muscle, fundamental for muscular regeneration and inducible source of IL-6 (Joe et al., 2010; Madaro et al., 2018).…”

Section: Il-6/jak/stat Signaling Cascade In Skeletal Musclementioning

confidence: 99%

The JAK/STAT Pathway in Skeletal Muscle Pathophysiology

2019

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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.

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Signal transducer and activator of transcription 3 signaling as a potential target to treat muscle wasting diseases

Cited by 26 publications

References 41 publications

Denervation-activated STAT3–IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis

Denervation-activated STAT3–IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis

MicroRNA-125a-5p plays a role as a tumor suppressor in lung carcinoma cells by directly targeting STAT3

The JAK/STAT Pathway in Skeletal Muscle Pathophysiology

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