.png){kind=icon}
.png){kind=icon}
Return
Exercise-responsive skeletal muscle genes mechanistically linked to metabolic dysfunction-associated steatotic liver disease
.png){kind=icon}
PRE
AI
Z
C
Z
Z
J
Z
L
L
DOI：10.3748/wjg.v32.i13.113985.png)
.png){kind=icon}
Original request for help.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
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.
Keywords:
Metabolic dysfunction-associated steatotic liver disease
Myokines
Weighted gene co-expression network analysis
LAMA4
PECAM1
PXDN
THBS4
Journal
IF:
5.4
Papers:
2.1W
Citations:
5.1W
Organization
Cited Papers