β-Hydroxy-β-methylbutyrate facilitates PI3K/Akt-dependent mammalian target of rapamycin and FoxO1/3a phosphorylations and alleviates tumor necrosis factor α/interferon γ-induced MuRF-1 expression in C2C12 cells.
β-Hydroxy-β-methylbutyrate (HMB) prevents deleterious muscle responses under pathological conditions, including tumor- and chronic steroid therapy-related muscle losses. Here, we investigated the hypothesis that HMB may modulate the balance between protein synthesis and degradation in the PI3K/Akt-mediated mammalian target of rapamycin (mTOR) and FoxO1/FoxO3a-dependent mechanisms in differentiated C2C12 muscle cells. We also tested the effect of HMB on the expression of MuRF-1 and atrogin-1 in response to the inflammatory stress. β-Hydroxy-β-methylbutyrate up-regulated phosphorylation of Akt and mTOR, and these effects were completely abolished in the presence of PI3K inhibitor LY294002. β-Hydroxy-β-methylbutyrate also up-regulated FoxO1 and FoxO3a phosphorylation, and these changes were inhibited by LY294002. Although, unexpectedly, HMB failed to reduce the expressions of atrophy-related atrogin-1 messenger RNA and the protein response to the proinflammatory cytokines tumor necrosis factor α plus interferon γ, HMB did attenuate the MuRF-1 expression. Thus, HMB appears to restore the balance between intracellular protein synthesis and proteolysis, likely via activation of the PI3K/Akt-dependent mTOR and FoxO1/FoxO3a signaling pathway and the reduction of tumor necrosis factor α/interferon γ-induced MuRF-1 expression, thereby ameliorating aging-related muscle atrophy.
Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kaoru
K
Kimura
Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: xianwu@med.nagoya-u.ac.jp.
Xian Wu
XW
Cheng
Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Aiko
A
Inoue
Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Lina
L
Hu
Department of Sports Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Teruhiko
T
Koike
Department of Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: kuzuya@med.nagoya-u.ac.jp.
Masafumi
M
Kuzuya
D000375:Aging; D002460:Cell Line; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation; D014631:Valerates / Q000494:pharmacology*
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009124:Muscle Proteins; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; D014631:Valerates; C004961:beta-hydroxyisovaleric acid; D007371:Interferon-gamma; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
C2C12; Forkhead box class O; Phosphoinositide 3-kinase; Ubiquitin ligase; β-Hydroxy-β-methylbutyrate