Dataset Information

Data-Modeling Identifies Conflicting Signaling Axes Governing Myoblast Proliferation and Differentiation Responses to Diverse Ligand Stimuli.

ABSTRACT: Introduction:Skeletal muscle tissue development and regeneration relies on the proliferation, maturation and fusion of muscle progenitor cells (myoblasts), which arise transiently from muscle stem cells (satellite cells). Following muscle damage, myoblasts proliferate and differentiate in response to temporally-varying inflammatory cytokines, growth factors, and extracellular matrix cues, which stimulate a shared network of intracellular signaling pathways. Here we present an integrated data-modeling approach to elucidate synergies and antagonisms among proliferation and differentiation signaling axes in myoblasts stimulated by regeneration-associated ligands. Methods:We treated mouse primary myoblasts in culture with combinations of eight regeneration-associated growth factors and cytokines in mixtures that induced additive, synergistic, and antagonistic effects on myoblast proliferation and differentiation responses. For these combinatorial stimuli, we measured the activation dynamics of seven signal transduction pathways using multiplexed phosphoprotein assays and scored proliferation and differentiation responses based on expression of myogenic commitment factors to assemble a cue-signaling-response data compendium. We interrogated the relationship between these signals and responses by partial least-squares (PLS) regression modeling. Results:Partial least-squares data-modeling accurately predicted response outcomes in cross-validation on the training compendium (cumulative R 2 = 0.96). The PLS model highlighted signaling axes that distinctly govern myoblast proliferation (MEK-ERK, Stat3) and differentiation (JNK) in response to these combinatorial cues, and we confirmed these signal-response associations with small molecule perturbations. Unexpectedly, we observed that a negative feedback circuit involving the phosphatase DUSP6/MKP-3 auto-regulates MEK-ERK signaling in myoblasts. Conclusion:This data-modeling approach identified conflicting signaling axes that underlie muscle progenitor cell proliferation and differentiation.

SUBMITTER: Loiben AM

PROVIDER: S-EPMC6816730 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Data-Modeling Identifies Conflicting Signaling Axes Governing Myoblast Proliferation and Differentiation Responses to Diverse Ligand Stimuli.

Loiben Alexander M AM Soueid-Baumgarten Sharon S Kopyto Ruth F RF Bhattacharya Debadrita D Kim Joseph C JC Cosgrove Benjamin D BD

Cellular and molecular bioengineering 20170908 5

<h4>Introduction</h4>Skeletal muscle tissue development and regeneration relies on the proliferation, maturation and fusion of muscle progenitor cells (myoblasts), which arise transiently from muscle stem cells (satellite cells). Following muscle damage, myoblasts proliferate and differentiate in response to temporally-varying inflammatory cytokines, growth factors, and extracellular matrix cues, which stimulate a shared network of intracellular signaling pathways. Here we present an integrated ...[more]

PMID: 31719871

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Project description:Macrophage migration inhibitory factor (MIF) has been defined as an important chemokine-like function (CLF) chemokine with an essential role in monocyte recruitment and arrest. Adhesion of monocytes to the vessel wall and their transendothelial migration are critical in atherogenesis and many other inflammatory diseases. Chemokines carefully control all steps of the monocyte recruitment process. Those chemokines specialized in controlling arrest are typically immobilized on the endothelial surface, mediating the arrest of rolling monocytes by chemokine receptor-triggered pathways. The chemokine receptor CXCR2 functions as an important arrest receptor on monocytes. An arrest function has been revealed for the bona fide CXCR2 ligands CXCL1 and CXCL8, but genetic studies also suggested that additional arrest chemokines are likely to be involved in atherogenic leukocyte recruitment. While CXCR2 is known to interact with numerous CXC chemokine ligands, the CLF chemokine MIF, which structurally does not belong to the CXC chemokine sub-family, was surprisingly identified as a non-cognate ligand of CXCR2, responsible for critical arrest functions during the atherogenic process. MIF was originally identified as macrophage migration inhibitory factor (this function being eponymous), but is now known as a potent inflammatory cytokine with CLFs including chemotaxis and leukocyte arrest. This review will cover the mechanisms underlying these functions, including MIF's effects on LFA1 integrin activity and signal transduction, and will discuss the structural similarities between MIF and the bona fide CXCR2 ligand CXCL8 while emphasizing the structural differences. As MIF also interacts with CXCR4, a chemokine receptor implicated in CXCL12-elicited lymphocyte arrest, the arrest potential of the MIF/CXCR4 axis will also be scrutinized as well as the recently identified role of pericyte MIF in attracting leukocytes exiting through venules as part of the pericyte "motility instruction program."

Project description:BackgroundTyrosine kinase inhibitors (TKIs) are effective therapies with demonstrated antineoplastic activity. Nilotinib is a second-generation FDA-approved TKI designed to overcome Imatinib resistance and intolerance in patients with chronic myelogenous leukemia (CML). Interestingly, TKIs have also been shown to be an efficient treatment for several non-malignant disorders such fibrotic diseases, including those affecting skeletal muscles.MethodsWe investigated the role of Nilotinib on skeletal myogenesis using the well-established C2C12 myoblast cell line. We evaluated the impact of Nilotinib during the time course of skeletal myogenesis. We compared the effect of Nilotinib with the well-known p38 MAPK inhibitor SB203580. MEK1/2 UO126 and PI3K/AKT LY294002 inhibitors were used to identify the signaling pathways involved in Nilotinib-related effects on myoblast. Adult primary myoblasts were also used to corroborate the inhibition of myoblasts fusion and myotube-nuclei positioning by Nilotinib.ResultsWe found that Nilotinib inhibited myogenic differentiation, reducing the number of myogenin-positive myoblasts and decreasing myogenin and MyoD expression. Furthermore, Nilotinib-mediated anti-myogenic effects impair myotube formation, myosin heavy chain expression, and compromise myotube-nuclei positioning. In addition, we found that p38 MAPK is a new off-target protein of Nilotinib, which causes inhibition of p38 phosphorylation in a similar manner as the well-characterized p38 inhibitor SB203580. Nilotinib induces the activation of ERK1/2 and AKT on myoblasts but not in myotubes. We also found that Nilotinib stimulates myoblast proliferation, a process dependent on ERK1/2 and AKT activation.ConclusionsOur findings suggest that Nilotinib may have important negative effects on muscle homeostasis, inhibiting myogenic differentiation but stimulating myoblasts proliferation. Additionally, we found that Nilotinib stimulates the activation of ERK1/2 and AKT. On the other hand, we suggest that p38 MAPK is a new off-target of Nilotinib. Thus, there is a necessity for future studies to investigate the long-term effects of TKIs on skeletal muscle homeostasis, along with potential detrimental effects in cell differentiation and proliferation in patients receiving TKI therapies.

Dataset Information

Data-Modeling Identifies Conflicting Signaling Axes Governing Myoblast Proliferation and Differentiation Responses to Diverse Ligand Stimuli.

Publications

Data-Modeling Identifies Conflicting Signaling Axes Governing Myoblast Proliferation and Differentiation Responses to Diverse Ligand Stimuli.

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