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Exercise-responsive skeletal muscle genes mechanistically linked to metabolic dysfunction-associated steatotic liver disease
Jia-Hui Zhang, Kang Chen, Xiao-Min Zhu, Huan Zhou, Jia-Mi Jiang, Yu-Qing Zou, Ke-Rong Liu, Le Zhang, Yun Li
Jia-Hui Zhang, Huan Zhou, Yu-Qing Zou, Yun Li, Department of Pediatric Laboratory, Affiliated Children’s Hospital of Jiangnan University, Wuxi Children’s Hospital, Wuxi Key Laboratory of Genetic and Metabolic Diseases in Children, Wuxi 214023, Jiangsu Province, China
Kang Chen, Le Zhang, Wuxi Medical Center, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
Xiao-Min Zhu, Department of Pediatric Surgery, Affiliated Children’s Hospital of Jiangnan University, Wuxi Children’s Hospital, Wuxi 214023, Jiangsu Province, China
Jia-Mi Jiang, State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Jiangnan University, Wuxi 214122, Jiangsu Province, China
Ke-Rong Liu, Department of Endocrinology, Affiliated Children’s Hospital of Jiangnan University, Wuxi Children’s Hospital, Wuxi Key Laboratory of Genetic and Metabolic Diseases in Children, Wuxi 214023, Jiangsu Province, China
Co-first authors: Jia-Hui Zhang and Kang Chen.
Co-corresponding authors: Le Zhang and Yun Li.
Author contributions: Zhang JH conceived and designed the study, performed western blot analysis; Chen K and Zhu XM performed the experiments; Zhang JH and Chen K conducted the bioinformatic analysis; Chen K, Zhou H and Jiang JM performed animal experiment; Chen K performed enzyme-linked immunosorbent assay analysis; Zou YQ performed quantitative polymerase chain reaction analysis; Zhang JH and Li Y wrote the manuscript; Liu KR and Zhang L review, editing and proofreading the manuscript; Zhang L supervised the study; Zhang JH, Zhang L and Li Y provided the funding support and supervised the study; Zhang JH, Chen K contributed equally to this manuscript, they are co-first authors of this manuscript; Zhang L, and Li Y contributed equally to this manuscript, they are co-corresponding authors of this study; all authors have read and approved the final version to be published.
Supported by the Wuxi Science and Technology Development Fund, No. K20241001 and No. Y20232026; Jiangsu Medical Association Pediatric Medicine Phase II Scientific Research Special Fund Project, No. SYH-32034-0106 (2024010); Top Talent Support Program for Young and Middle-Aged People of Wuxi Health Committee, No. HB2023091 and No. BJ2023090; and Medical Key Discipline Program of Wuxi Health Commission, No. ZDXK2021007.
Institutional animal care and use committee statement: All relevant international, national, and institutional guidelines for the care and use of animals were strictly observed. This study was approved and conducted in accordance with the ethical standards of the Affiliated Children’s Hospital of Jiangnan University (Ethical Review Consent No. WXCH2024-05-101).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: All data generated during this study are available from the corresponding authors upon reasonable request.
Corresponding author: Yun Li, PhD, Research Assistant Professor, Department of Pediatric Laboratory, Affiliated Children’s Hospital of Jiangnan University, Wuxi Children’s Hospital, Wuxi Key Laboratory of Genetic and Metabolic Diseases in Children, No. 299 Qingyang Road, Liangxi District, Wuxi 214023, Jiangsu Province, China.
yunli_med@jiangnan.edu.cn
Received: September 11, 2025
Revised: November 17, 2025
Accepted: January 12, 2026
Published online: April 7, 2026
Processing time: 197 Days and 13.1 Hours
BACKGROUND
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver disease that progresses from simple steatosis to inflammation, fibrosis, and cirrhosis. Currently, no effective targeted therapy is available. Exercise is a well-recognized non-pharmacological intervention with clear benefits. However, the biological mechanisms by which skeletal muscle responds to regular exercise and contributes to MASLD improvement remain poorly understood.
AIM
To identify exercise-responsive biomarkers in skeletal muscle associated with MASLD and explore their diagnostic and therapeutic potential.
METHODS
We analyzed skeletal muscle transcriptomic datasets from the gene expression omnibus. Differentially expressed genes (DEGs) were detected and then analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment methods. To identify key genes, we employed weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression. Correlation with diagnostic efficacy was performed utilizing a validation group and receiver operating characteristic (ROC) analysis. Finally, an obese mouse model was established and subjected to endurance aerobic training. Gastrocnemius muscle tissue was validated at the messenger RNA, protein, and secretion levels to confirm the identified biomarkers.
RESULTS
Transcriptomic analysis identified 61 DEGs between pre-exercise and post-exercise samples, with 40 upregulated and 21 downregulated genes. GO enrichment analysis showed that extracellular matrix (ECM) organization and collagen fibril formation were significantly enriched. KEGG pathway analysis further highlighted cytoskeleton dynamics in muscle cells and ECM-receptor interactions. Integrated DEGs, WGCNA and LASSO analysis identified 12 hub genes. Validation cohort and ROC analysis demonstrated strong diagnostic performance for nine hub genes (COL3A1, COL1A2, BGN, LAMB1, PECAM1, LAMA4, THBS4, PXDN and THY1). In the mouse model, three hub genes (Lama4, Pecam1 and Pxdn) were significantly upregulated, while Thbs4 was downregulated after exercise in skeletal muscle tissue.
CONCLUSION
This study identified four exercise-responsive skeletal muscle-expressed genes (LAMA4, PECAM1, PXDN and THBS4). These genes are mechanistically associated with MASLD and may serve as myokine-like candidates. Our research offers new perspectives on the pathophysiology of MASLD and suggest possible strategies for precision diagnosis and therapy.
Core Tip: This study identified four exercise-responsive skeletal muscle-expressed genes (LAMA4, PECAM1, PXDN and THBS4), which were mechanistically linked to metabolic dysfunction-associated steatotic liver disease (MASLD). These genes may serve as myokine-like candidates, shedding light on the molecular pathways by which exercise mediates metabolic adaptation in MASLD. The findings provided novel insights into the pathophysiology of MASLD and suggested these biomarkers as promising candidates for precision diagnostics and therapeutic interventions.
