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TAK-1/p38/NFkappaB Signaling Inhibits Myoblast Differentiation By Increasing Levels of Activin A

Trendelenburg, Anne-Ulrike and Meyer, Angelika and Jacobi, Carsten and Feige, Jerome and Glass, David (2012) TAK-1/p38/NFkappaB Signaling Inhibits Myoblast Differentiation By Increasing Levels of Activin A. Skeletal Muscle, 2 (1). p. 3. ISSN 2044-5040

Abstract

Background:
Skeletal muscle differentiation is required for the regeneration of myofibers after injury. The differentiation capacity of satellite cells is impaired in settings of old age, which is at least one factor in the onset of sarcopenia – the age-related loss of skeletal muscle mass and major cause of frailty. One important cause for impaired regeneration is increased TGF-beta accompanied by reduced Notch signaling. Pro-inflammatory cytokines are also upregulated in ageing which led us hypothesize their potential contribution to impaired regeneration in sarcopenia. Thus, we have further analysed the muscle differentiation-inhibition pathway by pro-inflammatory cytokines in human skeletal muscle cells
Methods:
We studied the modulation of human skeletal muscle cell (HuSKMCs) differentiation by pro-inflammatory cytokines IL-1alpha and TNF-alpha. Grade of differentiation was determined by either imaging (fusion index) or creatine kinase (CK) activity, a marker of muscle differentiation. Secretion of TGF-beta proteins during differentiation was assessed by using a TGF-beta responsive reporter gene assay and further identified by means of pharmacological and genetic inhibitors. In addition, signaling events were monitored both in HuSKMC cultures as well as samples from a rat sarcopenia study by Western Blots and RT-PCR.
Results:
The pro-inflammatory cytokines IL-1α and TNF-α block differentiation of human myoblasts into myotubes. This anti-differentiation effect requires the activation of TAK-1. Using pharmacological and genetic inhibitors, the TAK-1 pathway could be traced to p38 and NFkappaB. Surprisingly, the anti-differentiation effect of the cytokines required the transcriptional upregulation of Activin A, which in turn acted through its established signaling pathway – ActRII/ALK/SMAD. Inhibition of Activin A signaling is able to rescue human myoblasts treated with IL-1alpha or TNF-α, resulting in normal differentiation into myotubes. Studies in aged rats as a model of sarcopenia confirmed that this pro-inflammatory cytokine pathway identified is activated during aging.
Conclusions:
This study demonstrates an unexpected connection between cytokine and
Activin signaling, demonstrating a new mechanism by which cytokines affect skeletal muscle, establishing the physiologic relevance of this pathway in sarcopenia.

Item Type: Article
Related URLs:
Keywords: Human skeletal muscle, Sarcopenia, Activin A, TAK-1, Differentiation, TNF-alpha, IL-1alpha
Related URLs:
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/3124

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