Calcineurin activates NF-kappaB in skeletal muscle C2C12 cells

Abstract

Calcineurin (CnA) is an important signalling molecule in skeletal muscle, in the promotion of differentiation, slow-fibre phenotype and possibly fibre hypertrophy. We found that stable expression of constitutively active CnA in muscle C2C12 cells strongly activated NF-kappaB, a key mediator of muscle wasting. NF-kappaB activation by CnA was associated with elevated phospho-IkappaBalpha, and could be repressed by specific genetic (porZAKI-4 and porDSCR1) and chemical (cyclosporin A) inhibitors of CnA, but tumour necrosis factor-alpha (TNF-alpha) appeared not to be a key component in the cross-talk. Functionally, CnA-induced NF-kappaB activation seemed to interfere with terminal muscle differentiation. We therefore showed a functional interaction between the CnA and NF-kappaB pathways in skeletal muscle cells, which involved opposing phenotypic effects of CnA.