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

Wang, Wenjing, Liew, Wei Lin, Huang, Shiqi, Chan, Edmund, Li Min Tan, Amelia, Tian, Chi, Tong, Yihan, Zhang, Yuntian, Liu, Fei, Qin, Yixian, Jun Leong Ou, Sean, Sadananthan, Suresh Anand, Velan, Sambasivam Sendhil, Venkataraman, Kavita, Langley, Sarah ORCID: https://orcid.org/0000-0003-4419-476X, Enrico, Petretto, Hoon, Shawn, Tham, Kwang Wei, Chong, Yap Seng, Lee, Yung Seng, Leow, Melvin Khee-Shing, Sim, Xueling, Khoo, Chin Meng, Tai, E Shyong, Khoo, Eric Yin Hao, Liu, Mei Hui and Liu, Boxiang 2025. Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues. Cell Genomics , 100951. 10.1016/j.xgen.2025.100951

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Biosciences
Publisher:	Cell Press
ISSN:	2666-979X
Date of First Compliant Deposit:	29 July 2025
Date of Acceptance:	30 June 2025
Last Modified:	31 Jul 2025 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/180125

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