TNF-α and glucocorticoid receptor interaction in L6 muscle cells: A cooperative downregulation of myosin heavy chain

Abstract

Sepsis is associated with increased expression of TNF-α with subsequent activation of nuclear factorkappa B (NF-κB). The glucocorticoid receptor (GR) and NF-κB function as mutual antagonists and induction of the latter is believed to play a major role in the acquired glucocorticoid resistance that occurs in some septic patients. GR expression and function has been reported to be elevated in septic muscle suggesting a limited effect of the activated NF-κB on GR function in this context. In this study, the L6 myocyte cell line was used as an in vitro model for a sepsis-like condition in skeletal muscle. While short or long term treatment with TNF-α had no effect on GR expression, glucocorticoid-dependent downregulation of GR occurred with a kinetic profile that is accelerated relative to that observed in most cells. This downregulation was not affected by co-treatment or prior priming of L6 cells with TNF-α. The synthetic glucocorticoid, dexamethasone (DEX) blunted TNF-α-stimulated NF-κB activation in L6 cells. However, although effective at activating an NF-κB transcriptional response, TNF-α treatment exerted a minimal effect in myoblasts and no effect in myotubes on GR transcriptional activity. This limited impact of TNF-α on GR activity was not universal as TNF-α and DEX exerted an additive effect on the reduction in myosin heavy chain (MHC) protein expression caused by either agent alone. Thus, the selective perseverance of GR function in the presence of increased levels of glucocorticoids and TNF-α during sepsis or other inflammatory states may exacerbate muscle protein breakdown.

Roles of GILZ in protein metabolism of L6 muscle cells exposed to serum from septic rats

“…It has been reported that GR expression is downregulated in L6 myocyte cells when treated with the synthetic glucocorticoid, DEX (Dekelbab et al, 2007). Consistent with this, Figure 4.…”

“…In addition, GR expression also increases in L6 skeletal muscle cells in vitro when treated with serum from septic rats. However, downregulation of GR was observed in cells cultured in the resting state (Dekelbab et al, 2007). The findings above suggest that GC levels rise in the body during sepsis, but GC resistance appears in inflammatory cells, thus anti-inflammatory factor GC does not suppress the excessive inflammatory response.…”

Glucocorticoid-induced Leucine Zipper (GILZ) and Long GILZ Inhibit Myogenic Differentiation and Mediate Anti-myogenic Effects of Glucocorticoids

“…Collectively, our data support the idea that GILZ/L-GILZ could be targets for future therapies of myopathies and for control of GC-mediated antimyogenic effects. Indeed, GC treatment has been reported to result in reduced myogenesis and inhibition of the activation of muscle satellite cells (7,8). These observations might call for a reconsideration of anti-inflammatory GC therapy of myopathies as well for new therapeutic strategies aimed to counter GC side effects at the muscle tissue level.…”

“…Nevertheless, GC effects on differentiating myoblasts have not been extensively investigated. In fact, despite the evidence that dexamethasone (DEX) treatment results in reduced myogenesis and inhibition of the activation of the adult stem cells in skeletal muscle tissue known as satellite cells (7,8), the molecular determinants of these biological effects are still poorly understood.…”

Apoptosis and differentiation of Xenopus tail-derived myoblasts by thyroid hormone

“…1). In mammals, the rat L6 myoblastic cell line expresses MHC in both growth and differentiation media (Dekelbab et al 2007). In contrast, mouse C2C12 myoblasts do not express MHC in growth medium, but they do express it in differentiation medium (Artaza et al 2002).…”