Genetic regulation of human skeletal muscle: from bulk QTLs to single-nucleus resolution

Although lifestyle-induced weight loss reduces type 2 diabetes risk, how genetic variation shapes gene expression and splicing responses to weight loss remains poorly understood, particularly in Asian populations. In the first part of this talk, I will present our recently published work (Cell Genomics, 2025) in which we profiled skeletal muscle transcriptomes from 54 overweight/obese Asian individuals before and after a 16-week lifestyle intervention in the Singapore Adult Metabolism Study (SAMS). The intervention resulted in ~10% weight loss and ~30% improvement in insulin-stimulated glucose uptake. We identified 505 differentially expressed genes enriched in mitochondrial function and insulin sensitivity pathways, mapped cis-eQTLs and cis-sQTLs that are shared or condition-specific, and integrated these regulatory variants with GWAS signals for metabolic traits to pinpoint candidate causal genes and mechanisms. In the second part, I will introduce our ongoing effort to build a comprehensive single-nucleus and spatial transcriptomic atlas of human skeletal muscle. Using snRNA-seq from over 300 biopsies spanning lean and obese individuals across three Asian ancestries, we have profiled more than one million nuclei and annotated over 20 cell types capturing substantial cellular heterogeneity across ancestry, adiposity, and metabolic states. We are now extending this resource with spatial transcriptomics (MERFISH and Xenium) on paired pre- and post-intervention samples to spatially resolve cell-type-specific regulatory programs and microenvironment remodeling during weight loss. Together, these efforts establish the first longitudinal, ancestry-diverse single-nucleus and spatial regulatory reference for Asian human skeletal muscle.