The stress
kinase c-jun N-terminal kinase (JNK) was recently shown to be involved in the pathophysiology of major inflammatory conditions, including
Alzheimer's disease,
stroke,
obesity, and type II diabetes. However, the role of JNK in regulating inflammatory events in skeletal muscle is only beginning to be explored.
IGF-I is the major
hormone that promotes muscle growth and development. Here we used a novel, JNK interacting
protein (JIP)-derived JNK
peptide inhibitor to establish that JNK suppresses the biological activity of
IGF-I in skeletal muscle progenitor cells. In these myoblasts,
TNFalpha and its downstream receptor substrates, neutral-
sphingomyelinase (N-SMase) and N-acetyl-d-
sphingosine (C2-ceramide), induce
JNK kinase activity in a time-dependent manner. Consistent with these results,
TNFalpha induces JNK binding to
insulin receptor substrate 1 (IRS-1) but is unable to inhibit
IGF-I-induced IRS-1
tyrosine phosphorylation in myoblasts that are treated with the JNK
peptide inhibitor. More importantly, JNK activation induced by
TNFalpha,
C2-ceramide, and N-SMase is associated with reduced expression of the critical muscle
transcription factor myogenin as well as the
differentiation marker myosin heavy chain (MHC). The JNK
peptide inhibitor, but not the control
peptide, completely reverses this inhibition of both
myogenin and MHC. In the absence of
IGF-I,
TNFalpha,
C2-ceramide, N-SMase and the JNK inhibitor are inactive, as shown by their inability to affect IRS
tyrosine phosphorylation and
protein expression of
myogenin and MHC. These results establish that the resistance of muscle progenitor cells to
IGF-I, which is caused by inflammatory stimuli, is mediated by the JNK stress
kinase pathway.