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.

No abstract

Although disruption of the microtubule (MT) array inhibits myogenesis in myocytes, the relationship between the assembly of microtubules (MT) and the organization of the contractile filaments is not clearly defined. We now report that the assembly of mature myofibrils in hypertrophic cardiac myocytes is disrupted by myoseverin, a compound previously shown to perturb the MT array in skeletal muscle cells. Myoseverin treated cardiac myocytes showed disruptions of the striated Z-bands containing a-actinin and desmin and the localization of tropomyosin, titin and myosin on mature sarcomeric filaments. In contrast, MT depolymerization by nocodazole did not perturb sarcomeric filaments. Similarly, expression of constitutively active stathmin as a non-chemical molecular method of MT depolymerization did not prevent sarcomere assembly. The extent of MT destabilization by myoseverin and nocodazole were comparable. Thus, the effect of myoseverin on sarcomere assembly was independent of its capacity for MT inhibition. Furthermore, we found that upon removal of myoseverin, sarcomeres reformed in the absence of an intact MT network. Sarcomere formation in cardiac myocytes therefore, does not appear to require an intact MT network and thus we conclude that a functional MT array appears to be dispensable for myofibrillogenesis. Cell Motil. Cytoskeleton 65: 40-58, 2008. '