Multifaceted roles of TNF-alpha in myoblast destruction: a multitude of signal transduction pathways

C E H Stewart, P V Newcomb, J M P Holly

Research output: Contribution to journalArticle (Academic Journal)peer-review

83 Citations (Scopus)


In catabolic conditions, such as cancer cachexia, a balance favouring a cytokine environment culminates in muscle destruction. Utilising an in vitro model to mimic muscle wasting, we elucidate here the multifaceted roles that one such cytokine, TNF-alpha, invokes in the degeneration process. Treatment of C2 skeletal myoblasts with TNF-alpha not only suppresses morphological and biochemical differentiation, but following an initial wave of proliferation, and of survival (24 h), induces apoptosis. Investigating the mechanisms underlying these diverse actions of TNF-alpha, we demonstrate that cell replication is dependent on rapid and sustained activation of MAP kinase. Map kinase is not, however, central to the death process, which is associated with a progressive rise in caspase-8 activity, and is accompanied by sustained activation of JNK1 and transient activation of JNK2. Caspase inhibition caused a dose responsive reduction in cell death, while inhibition of the JNKs caused a significant increase in apoptosis. We further report that PI3 kinase is not involved in conferring early protection against TNF-alpha-induced death. By contrast, inhibition of NF-kappaB in the presence of TNF-alpha culminates in increased cell cycle progression, decreased gadd45beta expression and significant and precociously increased cell death, when compared with TNF-alpha alone. Our results begin to characterise the mechanisms underlying the acute mitogenic and anti-apoptotic roles of TNF-alpha, which appear to be defined by a balance between MAP kinase, Jun kinase (JNK), NF-kappaB and gadd45beta. They establish that inhibition of any one of these molecules, as may occur following caspase activation, could eliminate vital stem cells required for skeletal muscle regeneration during chronic catabolic conditions.
Original languageEnglish
Pages (from-to)237-47
Number of pages11
JournalJournal of Cellular Physiology
Issue number2
Publication statusPublished - 2004


Dive into the research topics of 'Multifaceted roles of TNF-alpha in myoblast destruction: a multitude of signal transduction pathways'. Together they form a unique fingerprint.

Cite this