VEGF-B-mediated myofiber types involved in high-fat diet-induced hyperglycemia through PKA-NFATs signaling pathway
Abstract Background Hyperglycemia and insulin resistance are among the key phenotypes of obesity and type 2 diabetes (T2DM). Notably, skeletal muscle fiber-type composition is closely linked to insulin resistance. Vascular endothelial growth factor B (VEGF-B) has been shown to play an important role...
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BMC
2025-07-01
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| Online Access: | https://doi.org/10.1186/s13287-025-04455-7 |
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| author | Liu-liu Shi Yu-ting Sun Jia-nan Sun Jing Yue Wei Chen Kun Meng Long Chen Chang-qing Hu Rui Chen Dong-sheng Sun Cheng-bao Xu Wei Yuan Xin-li Li Dan Zhao Yan Wu Shi-bing Xi Xiao-ying Zhao Jun-ming Tang |
| author_facet | Liu-liu Shi Yu-ting Sun Jia-nan Sun Jing Yue Wei Chen Kun Meng Long Chen Chang-qing Hu Rui Chen Dong-sheng Sun Cheng-bao Xu Wei Yuan Xin-li Li Dan Zhao Yan Wu Shi-bing Xi Xiao-ying Zhao Jun-ming Tang |
| author_sort | Liu-liu Shi |
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| description | Abstract Background Hyperglycemia and insulin resistance are among the key phenotypes of obesity and type 2 diabetes (T2DM). Notably, skeletal muscle fiber-type composition is closely linked to insulin resistance. Vascular endothelial growth factor B (VEGF-B) has been shown to play an important role in T2DM. However, the effects of VEGF-B on myofiber types in individuals with obesity or T2DM remain unclear. This study aimed to investigate the effects and mechanisms of VEGF-B on myofiber-type formation and regeneration. Methods Male Vegfb (vascular endothelial growth factor B) gene knockout mice and wild-type C57BL/6 male mice were fed either a normal diet or a high-fat diet. Double immunofluorescence staining and RNA-seq of skeletal muscle tissue from these mice were used to evaluate the role of VEGF-B in myofiber type regulation. To investigate the effects of VEGF-B on myoblast differentiation, fusion, and type I slow-twitch fiber formation in vitro, we prepared a novel in vitro model by continuous single-dose administration of VEGF-B, which was matched with physiological conditions and high-fat diet-induced hyperglycemia in vivo. Results VEGF-B deficiency attenuated high-fat diet-induced loss of slow-twitch type I myofibers and improved hyperglycemia and insulin resistance in mice. Continuous low-concentration administration of VEGF-B isoforms (VEGF-B186 and VEGF-B167) enhanced myoblast differentiation, fusion and myotube formation in a dose-dependent manner, whereas higher concentrations inhibited these processes, with VEGF-B186 exhibiting more pronounced effects. Notably, elevated VEGF-B levels, particularly VEGF-B186, suppressed mainly slow-twitch type I myofiber formation. Mechanistic studies revealed that high-dose VEGF-B186 (100 ng/mL) reduced myoblast differentiation/fusion and slow-twitch fiber formation via PKA-NFAT-MyoG/MEF2C signaling. Furthermore, high-dose VEGF-B186 decreased the expression of glucose transporter type 4, glucose utilization, and mitochondrial function in a unique myoblast cell model, effects that were reversed by PKA activators and NFATc1/c2 overexpression. Conclusion These findings demonstrate that VEGF-B is a key regulator of myofiber type composition and metabolic homeostasis in the context of obesity or T2DM. The inhibitory effects of elevated VEGF-B186 on slow-twitch fiber formation and glucose metabolism underscore its pathological role in obesity-related metabolic dysregulation. These results support the therapeutic potential of targeting VEGF-B186—via inhibitors or monoclonal antibodies— for obesity and T2DM, which are characterized by slow-twitch fiber depletion. |
| format | Article |
| id | doaj-art-c4fac1bbdc4e4e0e9ca8e2444c490679 |
| institution | Kabale University |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj-art-c4fac1bbdc4e4e0e9ca8e2444c4906792025-08-20T04:01:25ZengBMCStem Cell Research & Therapy1757-65122025-07-0116112110.1186/s13287-025-04455-7VEGF-B-mediated myofiber types involved in high-fat diet-induced hyperglycemia through PKA-NFATs signaling pathwayLiu-liu Shi0Yu-ting Sun1Jia-nan Sun2Jing Yue3Wei Chen4Kun Meng5Long Chen6Chang-qing Hu7Rui Chen8Dong-sheng Sun9Cheng-bao Xu10Wei Yuan11Xin-li Li12Dan Zhao13Yan Wu14Shi-bing Xi15Xiao-ying Zhao16Jun-ming Tang17Hubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicinePediatrics Research Institute, Affiliated Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, School of Basic Medicine, Hubei University of MedicineAbstract Background Hyperglycemia and insulin resistance are among the key phenotypes of obesity and type 2 diabetes (T2DM). Notably, skeletal muscle fiber-type composition is closely linked to insulin resistance. Vascular endothelial growth factor B (VEGF-B) has been shown to play an important role in T2DM. However, the effects of VEGF-B on myofiber types in individuals with obesity or T2DM remain unclear. This study aimed to investigate the effects and mechanisms of VEGF-B on myofiber-type formation and regeneration. Methods Male Vegfb (vascular endothelial growth factor B) gene knockout mice and wild-type C57BL/6 male mice were fed either a normal diet or a high-fat diet. Double immunofluorescence staining and RNA-seq of skeletal muscle tissue from these mice were used to evaluate the role of VEGF-B in myofiber type regulation. To investigate the effects of VEGF-B on myoblast differentiation, fusion, and type I slow-twitch fiber formation in vitro, we prepared a novel in vitro model by continuous single-dose administration of VEGF-B, which was matched with physiological conditions and high-fat diet-induced hyperglycemia in vivo. Results VEGF-B deficiency attenuated high-fat diet-induced loss of slow-twitch type I myofibers and improved hyperglycemia and insulin resistance in mice. Continuous low-concentration administration of VEGF-B isoforms (VEGF-B186 and VEGF-B167) enhanced myoblast differentiation, fusion and myotube formation in a dose-dependent manner, whereas higher concentrations inhibited these processes, with VEGF-B186 exhibiting more pronounced effects. Notably, elevated VEGF-B levels, particularly VEGF-B186, suppressed mainly slow-twitch type I myofiber formation. Mechanistic studies revealed that high-dose VEGF-B186 (100 ng/mL) reduced myoblast differentiation/fusion and slow-twitch fiber formation via PKA-NFAT-MyoG/MEF2C signaling. Furthermore, high-dose VEGF-B186 decreased the expression of glucose transporter type 4, glucose utilization, and mitochondrial function in a unique myoblast cell model, effects that were reversed by PKA activators and NFATc1/c2 overexpression. Conclusion These findings demonstrate that VEGF-B is a key regulator of myofiber type composition and metabolic homeostasis in the context of obesity or T2DM. The inhibitory effects of elevated VEGF-B186 on slow-twitch fiber formation and glucose metabolism underscore its pathological role in obesity-related metabolic dysregulation. These results support the therapeutic potential of targeting VEGF-B186—via inhibitors or monoclonal antibodies— for obesity and T2DM, which are characterized by slow-twitch fiber depletion.https://doi.org/10.1186/s13287-025-04455-7VEGF-BMyoblast differentiation/fusionMyofiber typesHyperglycemiaObesityT2DM |
| spellingShingle | Liu-liu Shi Yu-ting Sun Jia-nan Sun Jing Yue Wei Chen Kun Meng Long Chen Chang-qing Hu Rui Chen Dong-sheng Sun Cheng-bao Xu Wei Yuan Xin-li Li Dan Zhao Yan Wu Shi-bing Xi Xiao-ying Zhao Jun-ming Tang VEGF-B-mediated myofiber types involved in high-fat diet-induced hyperglycemia through PKA-NFATs signaling pathway Stem Cell Research & Therapy VEGF-B Myoblast differentiation/fusion Myofiber types Hyperglycemia Obesity T2DM |
| title | VEGF-B-mediated myofiber types involved in high-fat diet-induced hyperglycemia through PKA-NFATs signaling pathway |
| title_full | VEGF-B-mediated myofiber types involved in high-fat diet-induced hyperglycemia through PKA-NFATs signaling pathway |
| title_fullStr | VEGF-B-mediated myofiber types involved in high-fat diet-induced hyperglycemia through PKA-NFATs signaling pathway |
| title_full_unstemmed | VEGF-B-mediated myofiber types involved in high-fat diet-induced hyperglycemia through PKA-NFATs signaling pathway |
| title_short | VEGF-B-mediated myofiber types involved in high-fat diet-induced hyperglycemia through PKA-NFATs signaling pathway |
| title_sort | vegf b mediated myofiber types involved in high fat diet induced hyperglycemia through pka nfats signaling pathway |
| topic | VEGF-B Myoblast differentiation/fusion Myofiber types Hyperglycemia Obesity T2DM |
| url | https://doi.org/10.1186/s13287-025-04455-7 |
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