Myoblast differentiation is influenced by a number of factors. For selleck example, insulin like growth factor 1 and low serum conditions promote differentiation, whereas transforming growth factor b and its family members, such as myostatin, block differentiation as do pro inflam matory cytokines. The role of the pro inflammatory cytokines, particularly in skeletal muscle differentiation, is controversial, as there are conflicting reports, documenting the capacity of these cytokines to either induce or inhibit dif ferentiation. Tumor necrosis factor a was found to be required for myogenesis, as shown by impaired regen eration in TNF a null animals. however, the concentration of TNF a required to promote differentia tion is apparently very low, and higher levels can have the opposite effect.

Inhibitors,Modulators,Libraries for example, whereas 0. 05 ng/ml of TNF a stimulated myogenesis, 0. 5 and 5 ng/ml caused inhibition. Similarly, the role of the downstream Inhibitors,Modulators,Libraries p38 pathway is under some dispute. On the one hand, the activity of p38 mitogen activated protein kinase is reportedly increased during myogenesis, and its inhibition was shown to inhibit the expression of select muscle specific genes and formation of multinucleated myotubes. During myogenesis, the activation of p38 MAPK promotes cell cycle exit by inducing the expression of a cyclin dependent kinase inhibitor, p21, which facilitates terminal differentia tion of muscle precursor cells. On the other hand, however, there are multiple reports of p38 inhibiting myo genesis.

for example, MAPK kinase kinase 1 sig naling through p38 was shown to result in the inactivation of E47 and thus repress myogenesis, and p38 phos phorylation of the transactivation domain of myogenic Inhibitors,Modulators,Libraries regulatory Inhibitors,Modulators,Libraries factor 4 represses transcription of myo genic genes. The phosphoinositide Inhibitors,Modulators,Libraries 3 kinase /AKT pathway is also activated during myogenesis, and insulin like growth factor 1, which initiates PI3K/AKT signal ing, is able to induce both differentiation of myoblasts, and hypertrophy of post differentiated myotubes. In post differentiated muscle, IGF 1/PI3K/AKT signaling opposes the action of TNF a/NF B activity, for example by inhibiting NF B mediated upregulation of the E3 ubiquitin ligases MuRF1 and MAFbx, which are required for skeletal muscle atrophy. TGF b activated kinase 1, a member of the MEKK family, was identified as a regulator of TGF b induced activation of MAPK. Recent studies have shown that TAK 1 is also a component of signal ing pathways leading to the activation of NF B and acti vator protein 1 in response to diverse all targets cytokines, including interleukin 1 and TNF a.