Flavones Inhibit LPS-Induced Atrogin-1/MAFbx Expression in Mouse C2C12 Skeletal Myotubes

Abstract

Summary Muscle atrophy is a complex process that occurs as a consequence of various stress events. Muscle atrophy-associated genes (atrogenes) such as atrogin-1/MAFbx and MuRF-1 are induced early in the atrophy process, and the increase in their expression precedes the loss of muscle weight. Although antioxidative nutrients suppress atrogene expression in skeletal muscle cells, the inhibitory effects of flavonoids on inflammation-induced atrogin-1/MAFbx expression have not been clarified. Here, we investigated the inhibitory effects of flavonoids on lipopolysaccharide (LPS)-induced atrogin-1/MAFbx expression. We examined whether nine flavonoids belonging to six flavonoid categories inhibited atrogin-1/ MAFbx expression in mouse C2C12 myotubes. Two major flavones, apigenin and luteolin, displayed potent inhibitory effects on atrogin-1/MAFbx expression. The pretreatment with apigenin and luteolin significantly prevented the decrease in C2C12 myotube diameter caused by LPS stimulation. Importantly, the pretreatment of LPS-stimulated myoblasts with these flavones significantly inhibited LPS-induced JNK phosphorylation in C2C12 myotubes, resulting in the significant suppression of atrogin-1/MAFbx promoter activity. These results suggest that apigenin and luteolin, prevent LPS-mediated atrogin-1/MAFbx expression through the inhibition of the JNK signaling pathway in C2C12 myotubes. Thus, these flavones, apigenin and luteolin, may be promising agents to prevent LPS-induced muscle atrophy.

The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass

“…Analyses of the protective effects of various flavonoids against lipopolysaccharide-induced MAFbx expression in skeletal myotubes revealed that two major flavones, apigenin and luteolin, prevented the decrease in myotube diameter and suppressed MAFbx promoter activity [143]. Similarly, the phyto-polyphenols epicatechin, epicatechin gallate, epigallocatechin gallate, and quercetin, were found to attenuate the increase in MuRF-1 and MAFbx induced in skeletal myotubes by three dimensional clinorotation [144].…”

“…Again, most of the evidence for these lifestyle effects on PS-341 [130] Dietary amino acids Leucine [129,[132][133] BCAA [136][137] Arginine [137] Glutamine [138] Taurine [139] Redox-related inhibitors N-acetylcysteine [39] Procysteine [120] Allopurinol [140] Phytochemicals Curcumin [141][142] Flavonoids [143] Polyphenols [144][145] PMI5011 [146] Ursolic acid [147] …”

Apigenin Ameliorates the Obesity‐Induced Skeletal Muscle Atrophy by Attenuating Mitochondrial Dysfunction in the Muscle of Obese Mice

“…reported that AP administration to obese mice ameliorated metabolic disease; decreases in protein acetylation and modulation of glucose and lipid homeostasis by increases in cellular NAD+ levels acted as inhibitors of the NAD + ase CD38. Although AP was suggested to have inhibitory effects on atrogin‐1/MAFbx expression and prevented the decrease in myotube diameter in C2C12 cells caused by lipopolysaccharide stimulation, the mechanisms of action of AP remain largely unknown and the biological effects of AP on obesity‐induced muscle atrophy have not yet been demonstrated in skeletal muscle.…”

Apigenin inhibits sciatic nerve denervation–induced muscle atrophy

“…7,8 Apigenin [5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one] is a naturally occurring plant flavone with anti-obesity, anti-inflammatory, antioxidant, and anti-cancer properties. [9][10][11] Moreover, Shiota et al 12 reported that apigenin (AP) has inhibitory effects on atrogin-1/MAFbx expression and prevents reductions in myotube diameter induced by lipopolysaccharide stimulation in the C2C12 murine cell line. However, the biological effect of AP in denervationinduced muscle atrophy has not yet been demonstrated.…”