Proinflammatory cytokines and skeletal muscle.
OBJECTIVE
Metabolic abnormalities leading to a catabolic syndrome with progressive muscular atrophy are a common final stage of various chronic diseases. Proinflammatory cytokines have been suggested both to induce and mediate local catabolic mechanisms. This review focuses on the role of proinflammatory cytokines in the development of muscular abnormalities resulting in a loss of muscle mass and function. In addition, the underlying molecular signaling pathways, their transcriptional regulation, and the cellular systems contributing to enhanced muscular protein breakdown are discussed.


RESULTS
Using transcriptional screening techniques, specific changes in gene expression have been identified that are characteristic of muscular wasting processes. Of particular interest is the atrophy-related and cytokine-inducible expression of a number of E3 ligases (e.g. atrogin-1, muscle ring finger protein 1), highly specific regulators of the ubiquitin-proteasome pathway, which target proteins for proteolytic breakdown by the proteasome. Furthermore, the activity of several transcription factors (e.g. nuclear factor kappa B) has been involved in specific transcriptional mechanisms of local inflammation and muscular atrophy. Finally, proinflammatory cytokines suppress the expression and function of the local anabolic growth factor insulin-like growth factor 1.


CONCLUSIONS
Pronounced catabolic effects of proinflammatory cytokines in various tissues contribute to local catabolism, with progressive atrophic alterations of the skeletal muscle in chronic disease states. Recent developments in this field have explored the underlying pathways of muscular wasting and have already resulted in the description of new molecular targets that might lead to new therapeutic options for the treatment of muscular atrophy.
Späte
Ulrike
U
The Forsyth Institute, Department of Cytokine Biology, Boston, Massachusetts, USA.
Schulze
P Christian
PC
D002908:Chronic Disease; D016207:Cytokines / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal; D009133:Muscular Atrophy / Q000201:enzymology / Q000276:immunology*; D009135:Muscular Diseases / Q000209:etiology / Q000276:immunology*; D014158:Transcription, Genetic; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D016207:Cytokines; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases