Endurance Exercise-Induced Fgf21 Promotes Skeletal Muscle Fiber Conversion through TGF-beta 1 and p38 MAPK Signaling Pathway

• Type of Material: Article
• Authors: Xiaomao Luo, Shanxi Agricultural University; Huiling Zhang, Shanxi Agricultural University; Xiaorui Cao, Shanxi Agricultural University; Ding Yang, China Agricultural University; Yi Yan, Shanxi Agricultural University; Jiayin Lu, Shanxi Agricultural University; Haidong Wang, Shanxi Agricultural University; Xiaonan Wang, Emory University
• Language: English
• Date: 2023-07-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/ijms241411401
• Title of Journal or Parent Work: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• Volume: 24
• Issue: 14
• Grant/Funding Information: This work was supported by grants from the Shanxi “1331 Project” (Grant No. 20211331-16), Shanxi Agricultural University “Science and Technology Innovation Enhancement Project” (Grant No. CXGC2023017), Shanxi Province Excellent Doctoral Work Award-Scientific Research Project (Grant No. SXYBKY2019001), as well as the Innovation Projects of College of Veterinary Medicine, Shanxi Agricultural University (Grant No. DY-M007).
• Keywords: Chemistry, Multidisciplinary; Science & Technology; p38 MAPK; Fgf21; REGENERATION; ADAPTATION; TGF-beta 1; fiber type; Chemistry; Life Sciences & Biomedicine; endurance exercise; Biochemistry & Molecular Biology; Physical Sciences
• Research Categories: Chemistry, Biochemistry; Biology, Molecular; Chemistry, General

Abstract

Fgf21 has been identified as playing a regulatory role in muscle growth and function. Although the mechanisms through which endurance training regulates skeletal muscle have been widely studied, the contribution of Fgf21 remains poorly understood. Here, muscle size and function were measured, and markers of fiber type were evaluated using immunohistochemistry, immunoblots, or qPCR in endurance-exercise-trained wild-type and Fgf21 KO mice. We also investigated Fgf21-induced fiber conversion in C2C12 cells, which were incubated with lentivirus and/or pathway inhibitors. We found that endurance exercise training enhanced the Fgf21 levels of liver and GAS muscle and exercise capacity and decreased the distribution of skeletal muscle fiber size, and fast-twitch fibers were observed converting to slow-twitch fibers in the GAS muscle of mice. Fgf21 promoted the markers of fiber-type transition and eMyHC-positive myotubes by inhibiting the TGF-β1 signaling axis and activating the p38 MAPK signaling pathway without apparent crosstalk. Our findings suggest that the transformation and function of skeletal muscle fiber types in response to endurance training could be mediated by Fgf21 and its downstream signaling pathways. Our results illuminate the mechanisms of Fgf21 in endurance-exercise-induced fiber-type conversion and suggest a potential use of Fgf21 in improving muscle health and combating fatigue.