Tumor necrosis factor‐alpha inhibits myogenic differentiation through MyoD protein destabilization

Abstract

Tumor necrosis factor alpha (TNFalpha) has been implicated as a mediator of muscle wasting through nuclear factor kappa B (NF-kappaB) -dependent inhibition of myogenic differentiation. The aim of the present study was to identify the regulatory molecule(s) of myogenesis targeted by TNFalpha/NF-kappaB signaling. TNFalpha interfered with cell cycle exit and repressed the accumulation of transcripts encoding muscle-specific genes in differentiating C2C12 myoblasts. Overexpression of a p65 (RelA) mutant lacking the transcriptional activation domain attenuated the TNFalpha-mediated inhibition of muscle-specific gene transcription. The ability of muscle regulatory factor MyoD to induce muscle-specific transcription in 10T1/2 fibroblasts was also disrupted by wild-type p65, demonstrating that NF-kappaB transcriptional activity interferes with the function of MyoD. Inhibition of muscle-specific gene expression by TNFalpha was restored by overexpression of MyoD, whereas endogenous MyoD protein abundance and stability were reduced by TNFalpha through increased proteolysis of MyoD by the ubiquitin proteasome pathway. Last, the inhibitory effects of TNFalpha on myogenic differentiation were demonstrated in a mouse model of skeletal muscle regeneration, in which TNFalpha caused a delay in myoblast cell cycle exit. These results implicate that TNFalpha inhibits myogenic differentiation through destabilizing MyoD protein in a NF-kappaB-dependent manner, which interferes with skeletal muscle regeneration and may contribute to muscle wasting.

Ubiquitin-Proteasome-mediated Degradation, Intracellular Localization, and Protein Synthesis of MyoD and Id1 during Muscle Differentiation

“…RT-PCR for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was also performed with the same samples as a control for the amount of reverse-transcribed cDNA present in the samples. the differentiation under abnormal or pathological conditions (23,24,26,27).…”

Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis

“…Molecular mechanisms involved in these processes are currently under investigation. It is likely that cytokines released by activated MPs infl uence myogenic cell behavior: TNF-α is mitogenic for myoblasts and inhibits their diff erentiation (71,72), IL-1β impairs myogenic diff erentiation through insulin-like growth factor-1 (73), and in vitro eff ects of TGF-β1 are more controversial, although in vivo neutralization of TGF-β1 in regenerating muscle was shown to reduce the diameter of regenerating myofi bers (74). Beyond cytokines, cyclooxygenase 2 and its metabolites may also play a role, as they were shown to be fusogenic and necessary for good muscle repair (75)(76)(77).…”

The epigenetic network regulating muscle development and regeneration

“…The importance of external cues in imparting to muscle progenitors the information necessary to differentiate into myofibers is emphasized by the role of injury-derived soluble substances and cytokines in regulating the myogenic potential of BMDC and satellite cells (Langen et al, 2001(Langen et al, , 2002(Langen et al, , 2004Coletti et al, 2002;Horsley et al, 2003;Broussard et al, 2004;Charge and Rudnicki, 2004;Sorci et al, 2004).…”