Implications of cross-talk between tumour necrosis factor and insulin-like growth factor-1 signalling in skeletal muscle.
1. Inflammation, particularly the pro-inflammatory cytokine tumour necrosis factor (TNF), increases necrosis of skeletal muscle. Depletion of inflammatory cells, such as neutrophils, cromolyn blockade of mast cell degranulation or pharmacological blockade of TNF reduces necrosis of dystrophic myofibres in the mdx mouse model of the lethal childhood disease Duchenne muscular dystrophy (DMD). 2. Insulin-like growth factor-1 (IGF-1) is a very important cytokine for maintenance of skeletal muscle mass and the transgenic overexpression of IGF-1 within muscle cells reduces necrosis of dystrophic myofibres in mdx mice. Thus, IGF-1 usually has the opposite effect to TNF. 3. Activation of TNF signalling via the c-Jun N-terminal kinase (JNK) can inhibit IGF-1 signalling by phosphorylation and conformational changes in insulin receptor substrate (IRS)-1 downstream of the IGF-1 receptor. Such silencing of IGF-1 signalling in situations where inflammatory cytokines are elevated has many implications for skeletal muscle in vivo. 4. The basis for these interactions between TNF and IGF-1 is discussed with specific reference to clinical consequences for myofibre necrosis in DMD and also for the wasting (atrophy) of skeletal muscles that occurs in very old people and in cachexia associated with inflammatory disorders.
Grounds
Miranda D
MD
School of Anatomy and Human Biology, The University of Western Australia, Crawley, Western Australia, Australia. mgrounds@anhb.uwa.edu.au
Radley
Hannah G
HG
Gebski
Bijanka L
BL
Bogoyevitch
Marie A
MA
Shavlakadze
Thea
T
D000818:Animals; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D009336:Necrosis; D020239:Receptor Cross-Talk / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I