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Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways.

ABSTRACT: Skeletal muscle weight loss is accompanied by small fiber size and low protein content. Alpha-ketoglutarate (AKG) participates in protein and nitrogen metabolism. The effect of AKG on skeletal muscle hypertrophy has not yet been tested, and its underlying mechanism is yet to be determined. In this study, we demonstrated that AKG (2%) increased the gastrocnemius muscle weight and fiber diameter in mice. Our in vitro study also confirmed that AKG dose increased protein synthesis in C2C12 myotubes, which could be effectively blocked by the antagonists of Akt and mTOR. The effects of AKG on skeletal muscle protein synthesis were independent of glutamate, its metabolite. We tested the expression of GPR91 and GPR99. The result demonstrated that C2C12 cells expressed GPR91, which could be upregulated by AKG. GPR91 knockdown abolished the effect of AKG on protein synthesis but failed to inhibit protein degradation. These findings demonstrated that AKG promoted skeletal muscle hypertrophy via Akt/mTOR signaling pathway. In addition, GPR91 might be partially attributed to AKG-induced skeletal muscle protein synthesis.

SUBMITTER: Cai X

PROVIDER: S-EPMC4881026 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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AKT signaling promotes epigenetic reprogramming via upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation

Project description:Phosphoinositide-3 kinase (PI3K)/AKT signaling participates in cellular proliferation, survival, and tumorigenesis as well as cellular reprogramming including generation of induced pluripotent stem cells (iPSCs). In this study, we revealed that activation of AKT in somatic cells undergoing reprogramming enhances epigenetic reprogramming. Activated AKT in reprogramming cells triggers elevated anabolic glucose metabolism, and, accordingly, increases the level of α-ketoglutarate (αKG) which is an essential cofactor for the enzymatic activity of the 5-methylcytosine (5mC) dioxygenase TET. Additionally, the level of TET was upregulated. Consistent with upregulated KG production and TET, we observed a genome-wide increase in 5-hydorxymethylcytosine (5hmC) which is an intermediate in the DNA demethylation process. Moreover, DNA methylation level at ES-cell super-enhancers of pluripotency-related genes was significantly decreased, leading upregulation of associated genes. Taken together, our results indicate that AKT signaling is associated with epigenetic regulation by hyperactivating TET at catalytical and transcriptional levels during the somatic cell reprogramming.

2021-09-29 | GSE161399 | GEO

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