Effects of extracellular orotic acid on acute contraction-induced adaptation patterns in C2C12 cells.
Dietary administration of orotic acid (OA), an intermediate in the pyrimidine biosynthetic pathway, is considered to provide a wide range of beneficial effects, including cardioprotection and exercise adaptation. Its mechanisms of action, when applied extracellularly, however, are barely understood. In this study, we evaluated potential effects of OA on skeletal muscle using an in vitro contraction model of electrically pulse-stimulated (EPS) C2C12 myotubes. By analyzing a subset of genes representing inflammatory, metabolic, and structural adaptation pathways, we could show that OA supplementation diminishes the EPS-provoked expression of inflammatory transcripts (interleukin 6, Il6; chemokine (C-X-C Motif) ligand 5, Cxcl5), and attenuated transcript levels of nuclear receptor subfamily 4 group A member 3 (Nr4A3), early growth response 1 (Egr1), activating transcription factor 3 (Atf3), and fast-oxidative MyHC-IIA isoform (Myh2). By contrast, OA had no suppressive effect on the pathogen-provoked inflammatory gene response in skeletal muscle cells, as demonstrated by stimulation of C2C12 myotubes with bacterial LPS. In addition, we observed a suppressive effect of OA on EPS-induced phosphorylation of AMP-activated protein kinase (AMPK), whereas EPS-triggered phosphorylation/activation of the mammalian target of rapamycin (mTOR) was not affected. Finally, we demonstrate that OA positively influences glycogen levels in EP-stimulated myotubes. Taken together, our results suggest that in skeletal muscle cells, OA modulates both the inflammatory and the metabolic reaction provoked by acute contraction. These results might have important clinical implications, specifically in cardiovascular and exercise medicine.
['Beiter|Thomas|T|', 'Hudemann|Jens|J|', 'Burgstahler|Christof|C|', 'Nieß|Andreas M|AM|', 'Munz|Barbara|B|']
D051700:Activating Transcription Factor 3 D000818:Animals D054365:Chemokine CXCL5 D004268:DNA-Binding Proteins D051766:Early Growth Response Protein 1 D004558:Electric Stimulation D005786:Gene Expression Regulation D015850:Interleukin-6 D051379:Mice D009119:Muscle Contraction D032448:Myoblasts, Skeletal D009419:Nerve Tissue Proteins D009963:Orotic Acid D011987:Receptors, Steroid D011988:Receptors, Thyroid Hormone D058570:TOR Serine-Threonine Kinases
Orotic acid Electrical pulse stimulation Skeletal muscle contraction