Cytokine-Induced Igf-I Resistance in Progenitor Muscle Cells
Strle, Klemen
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https://hdl.handle.net/2142/83585
Description
Title
Cytokine-Induced Igf-I Resistance in Progenitor Muscle Cells
Author(s)
Strle, Klemen
Issue Date
2005
Doctoral Committee Chair(s)
Kelley, Keith W.
Department of Study
Animal Sciences
Discipline
Animal Sciences
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Health Sciences, Immunology
Language
eng
Abstract
Cell growth and development are regulated by a complex network of interactions between the endocrine and immune systems. IGF-I is a critical anabolic factor that promotes growth and regeneration of skeletal muscle. Conversely, elevated levels of proinflammatory cytokines are associated with reduced anabolic activity of IGF-I and increased loss of muscle mass that occurs during aging and more prominently in cachectic AIDS and cancer patients. The loss of critical muscle mass limits mobility, decreases the quality of life and is closely associated with mortality independent of other parameters. Despite the widespread manifestations of wasting conditions, no specific targets and treatments to ameliorate the symptoms of these conditions have been identified. Here we show that low, physiologically relevant concentrations of TNFalpha and IL-1beta suppress the ability of IGF-I to induce global protein synthesis and expression of myogenic transcription factors that are needed for differentiation of murine progenitor muscle cells. We significantly extend these results by showing that cytokine-induced IGF-I resistance in myoblasts is mediated by activation of ceramide generating pathways, including N-SMase, A-SMase and de novo ceramide synthesis. The blockers of all three pathways suppress the ability of TNFalpha and IL-1beta to inhibit IGF-I-induced protein synthesis and expression of myogenic transcription factors, myogenin and MyoD. Furthermore we show that JNK is a key downstream intermediate by which TNFalpha and ceramide inhibit the IGF-I myogenic activity. TNFalpha, C2-ceramide and N-SMase potently induce JNK enzymatic activity. Active JNK associates with IRS-1, and this is a possible mechanism by which TNFalpha, and C2-ceramide, suppress the IGF-I-induced tyrosine phosphorylation of IRS-1. Indeed, a novel peptide inhibitor of JNK (I-JNK), potently suppressed JNK enzymatic activity and the ability of TNFalpha to inhibit tyrosine phosphorylation of IRS-1. More importantly, I-JNK suppresses the ability of TNFalpha, C2-ceramide and N-SMase to inhibit IGF-I-induced expression of myogenin. I-JNK also prevented the TNFalpha inhibition of IGF-I-induced expression of a marker of differentiation, MHC. Collectively these results demonstrate that JNK is a key downstream intermediate by which TNFalpha and C2-ceramide induce resistance to IGF-I anabolic activity in progenitor muscle cells.
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