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Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues.

Wenjing Wang·Wei Lin Liew·Shiqi Huang·Edmund Chan·Amelia Li Min Tan·Chi Tian·Yihan Tong·Yuntian Zhang·Fei Liu·Yixian Qin·Sean Jun Leong Ou·Suresh Anand Sadananthan·Sambasivam Sendhil Velan·Kavita Venkataraman·Sarah R Langley·Petretto Enrico·Shawn Hoon·Kwang Wei Tham·Yap Seng Chong·Yung Seng Lee·Melvin Khee-Shing Leow·Xueling Sim·Chin Meng Khoo·E Shyong Tai·Eric Yin Hao Khoo·Mei Hui Liu·Boxiang Liu
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Abstract

Weight loss through exercise and diet reduces the risk of type 2 diabetes, but the genetic regulation of gene expression and splicing in response to weight loss remains unclear in humans. We collected clinical data and skeletal muscle biopsies from 54 overweight/obese Asian individuals before and after a 16-week lifestyle intervention, which resulted in an average of ∼10% weight loss, accompanied by an ∼30% increase in insulin-stimulated glucose uptake. Improvements were observed in 118 of 252 clinical traits and six blood lipids. Transcriptomic analysis of paired skeletal muscle biopsies identified 505 differentially expressed genes enriched in mitochondrial function and insulin sensitivity. Thousands of muscle-specific expression/splicing quantitative trait loci (e/sQTLs) were detected pre- and post-intervention, including hundreds of lifestyle-responsive e/sQTLs. Notably, approximately 4.2% of eQTLs and 7.3% of sQTLs showed Asian specificity. Joint analysis with genome-wide association study (GWAS) identified 16 putative metabolic risk genes. Our study reveals gene-by-lifestyle interactions and how lifestyle modulates gene regulation in skeletal muscle.

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HumansMuscle, SkeletalExerciseMaleWeight LossFemaleMiddle AgedQuantitative Trait LociAdultGenome-Wide Association StudyObesityGene Expression RegulationPolymorphism, Single NucleotideDietInsulin ResistanceAsian-specific QTLgene-by-lifestyle interactionhuman intervention studylifestyle modificationsmetabolic diseaseskeletal muscle transcriptomicsweight lossJournal ArticleResearch Support, Non-U.S. Gov't

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Wenjing Wang, Wei Lin Liew, Shiqi Huang, Edmund Chan, Amelia Li Min Tan, Chi Tian, Yihan Tong, Yuntian Zhang, Fei Liu, Yixian Qin, Sean Jun Leong Ou, Suresh Anand Sadananthan, Sambasivam Sendhil Velan, Kavita Venkataraman, Sarah R Langley, Petretto Enrico, Shawn Hoon, Kwang Wei Tham, Yap Seng Chong, Yung Seng Lee, Melvin Khee-Shing Leow, Xueling Sim, Chin Meng Khoo, E Shyong Tai, Eric Yin Hao Khoo, Mei Hui Liu, Boxiang Liu. 2025-07-18. Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues.. https://doi.org/10.1016/j.xgen.2025.100951

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