Isoflavones derived from soy beans prevent MuRF1-mediated muscle atrophy in C2C12 myotubes through SIRT1 activation.
Proinflammatory cytokines are factors that induce ubiquitin-proteasome-dependent proteolysis in skeletal muscle, causing muscle atrophy. Although isoflavones, as potent antioxidative nutrients, have been known to reduce muscle damage during the catabolic state, the non-antioxidant effects of isoflavones against muscle atrophy are not well known. Here we report on the inhibitory effects of isoflavones such as genistein and daidzein on muscle atrophy caused by tumor necrosis factor (TNF)-α treatment. In C2C12 myotubes, TNF-α treatment markedly elevated the expression of the muscle-specific ubiquitin ligase MuRF1, but not of atrogin-1, leading to myotube atrophy. We found that MuRF1 promoter activity was mediated by acetylation of p65, a subunit of NFκB, a downstream target of the TNF-α signaling pathway; increased MuRF1 promoter activity was abolished by SIRT1, which is associated with deacetylation of p65. Of interest, isoflavones induced expression of SIRT1 mRNA and phosphorylation of AMP kinase, which is well known to stimulate SIRT1 expression, although there was no direct effect on SIRT1 activation. Moreover, isoflavones significantly suppressed MuRF1 promoter activity and myotube atrophy induced by TNF-α in C2C12 myotubes. These results suggest that isoflavones suppress myotube atrophy in skeletal muscle cells through activation of SIRT1 signaling. Thus, the efficacy of isoflavones could provide a novel therapeutic approach against inflammation-related muscle atrophy.
Department of Nutritional Physiology, Institute of Health Biosciences, the University of Tokushima Graduate School.
Katsuya
K
Hirasaka
Tasuku
T
Maeda
Chika
C
Ikeda
Marie
M
Haruna
Shohei
S
Kohno
Tomoki
T
Abe
Arisa
A
Ochi
Rie
R
Mukai
Motoko
M
Oarada
Shigetada
S
Eshima-Kondo
Ayako
A
Ohno
Yuushi
Y
Okumura
Junji
J
Terao
Takeshi
T
Nikawa
D000107:Acetylation; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000517:prevention & control; D007529:Isoflavones / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism / Q000517:prevention & control*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013025:Glycine max / Q000737:chemistry*; D051996:Transcription Factor RelA / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D000975:Antioxidants; D007529:Isoflavones; D009124:Muscle Proteins; D016328:NF-kappa B; D010936:Plant Extracts; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000263:Adenylate Kinase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1