The Mechanism of Stimulation of Myogenesis under the Action of Succinic Acid Through the Succinate Receptor SUCNR1

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In a study on cells of the C2C12 line, the effect of succinic acid on the processes of myogenesis was studied. In the concentration range of 10-1000 microns, succinic acid stimulated the process of myogenic differentiation, increasing the number of myogenesis factors MyoD (at all stages of myogenesis) and myogenin (at the stage of terminal differentiation). The Western blot method revealed specific succinate receptors SUCNR1 in C2C12 cells, the level of which decreased during myogenesis. When succinic acid was added to cells, the level of intracellular succinate did not change significantly and decreased during myogenic differentiation. Using a specific Gai protein inhibitor, pertussis toxin, it was found that stimulation of myogenesis of C2C12 under the action of succinic acid is realized through SUCNR1–Gai.

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Sobre autores

Yu. Abalenikhina

Ryazan State Medical University

Autor responsável pela correspondência
Email: abalenihina88@mail.ru
Rússia, Ryazan

M. Isaeva

Ryazan State Medical University

Email: abalenihina88@mail.ru
Rússia, Ryazan

P. Mylnikov

Ryazan State Medical University

Email: abalenihina88@mail.ru
Rússia, Ryazan

A. Shchulkin

Ryazan State Medical University

Email: abalenihina88@mail.ru
Rússia, Ryazan

E. Yakusheva

Ryazan State Medical University

Email: abalenihina88@mail.ru
Rússia, Ryazan

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2. Fig. 1. C2C12 cells before differentiation and at different stages of differentiation. Phase-contrast microscopy; 200×. Romanovsky-Giemsa staining of nuclei; L, length of myoblasts; B, width of myoblasts

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3. Fig. 2. Results of western blot analysis of the relative amounts of MyoD (a), MyoG (b), MYH (c), SUCNR1 (d) as a function of the day of differentiation of C2C12 cells. * p < 0.05 - compared to control (before differentiation); ^ p < 0.05 - compared to the first day of differentiation; ˅ p < 0.05 - compared to the fourth day of differentiation

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4. Fig. 3. Results of Western blot analysis of the relative amounts of MyoD and SUCNR1 on days 1 (a) and 4 (b) of differentiation; MYH, MyoG, SUCNR1 - on day 7 of differentiation (c) upon exposure of C2C12 cells to succinic acid at concentrations of 10, 100, 1000 μM. *p < 0.05 - compared to the values of the corresponding day of differentiation without the addition of succinic acid

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5. Fig. 4. Succinate concentration in C2C12 cells during their myogenic differentiation when succinic acid was added to nutrient medium at concentrations of 10 (a), 100 (b) and 1000 (c) μM (detection method - HPLC-MS/MS). * p < 0.05; ** p < 0.01 - statistically significant differences between groups

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6. Fig. 5. Results of Western blot analysis of the relative amounts of MyoD and SUCNR1 on days 1 (a) and 4 (b) of differentiation; MYH, MyoG, SUCNR1 - on day 7 of differentiation (c) when succinic acid at concentrations of 10, 100, 1000 μM, pertussis toxin (Pertussis toxin (PT), 100 ng/ml) and their combined application were applied to C2C12 cells. * p < 0.05 - compared to the values of the corresponding day of differentiation without succinic acid addition

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7. Fig. 6. Inositol monophosphate concentration in C2C12 cells during their myogenic differentiation when succinic acid was added to the nutrient medium at concentrations of 10, 100 and 1000 μM (detection method - HPLC-MS/MS). * p < 0.01 - statistically significant differences with the values of cells before succinate addition, # p < 0.01 - statistically significant differences with the values when succinic acid (100 μM) + pertussis toxin (100 ng/ml) was added

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8. Fig. 7. Putative mechanism of action of succinic acid on the process of myogenic differentiation of C2C12 cells. AC, adenylate cyclase; FLS, phospholipase C; PIF2, phosphatidylinositol-1,5-diphosphate; DAG, diacylglycerol; IF3, inositol-3-phosphate. Mechanism of action via Gαi protein is indicated by bold arrow; mechanism of action via Gγβ protein is indicated by thin arrow; mechanism of action via Ca2+-dependent proteins is indicated by dashed arrow

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9. Fig. 8. C2C12 cells before differentiation (a) and upon stimulation of myogenesis by the addition of 100 μM succinate (b). Phase-contrast microscopy; 200×. Romanovsky-Giemsa staining of nuclei; L - length of myoblasts, B - width of myoblasts

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