Glutamine Promotes Myogenesis in Myoblasts Through Glutaminolysis-Mediated Histone H3 Acetylation That Enhances Myogenin Transcription

Journal article

Background/Objectives: Plasma glutamine levels in skeletal muscle change in response to exercise intensity and duration, both in physiological and pathological states. Glutamine contributes to muscle differentiation and regeneration; however, the mechanisms underlying this process remain unclear. This study investigated the role of glutamine glutaminolysis in myogenic differentiation, with a focus on epigenetic regulation of myogenin gene expression. Methods: C2C12 myoblasts were differentiated into myotubes using media containing various concentrations of glutamine, glutamate, or dimethyl 2-oxoglutarate (DM-α-KG), a cell-permeable analog of α-ketoglutarate. Results: Glutamine, glutamate, and DM-α-KG promoted C2C12 myoblast differentiation in a concentration-dependent manner, whereas the glutaminase inhibitor CB-839 suppressed differentiation. 4 mM glutamine increased myogenin mRNA expression by about 5-fold. CB-839 also inhibited glutamine-induced expression of myogenin but did not influence the effects of glutamate or DM-α-KG. Furthermore, glutamine increased histone H3 lysine 27 acetylation (H3K27ac) by about two-fold, whereas CB-839 (200 nM) and A-485 (10 µM), a CBP/p300 histone acetyltransferase inhibitor, reduced H3K27ac levels by about half. These results indicate that glutamine not only serves as a structural amino acid for muscle formation but also enhances myogenin transcription through epigenetic mechanisms. Conclusions: This report demonstrates glutaminolysis-dependent histone H3 acetylation, which induces myogenin transcription in myoblasts. These results, connecting glutamine supplementation during resistance training, may make it an effective strategy to accelerate muscle regeneration.

Authors: Takatoya, M; Kasugai, T; Arai, D; Kasuga, U; Miyaura, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: Nutrients
• Volume: 17
• Issue: 23
• Pages: 3673-3673
• Article number: 3673
• Publication date: 2025-11-24
• Acceptance date: 2025-11-20
• DOI: 10.3390/nu17233673
• EISSN: 2072-6643
• ISSN: 2072-6643
• Language: English
• Keywords: C2C12 myoblast; epigenetic regulation; glutaminolysis; histone H3 acetylation; glutamine