bioRxiv : the preprint server for biology · 2026
A full-length single nuclei transcriptomic atlas of human skeletal muscle insulin resistance.
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Whytock Katie L, Divoux Adeline, Vazquez James, Hopf Meghan, Viggars Mark R, Gutierrez-Monreal Miguel A, Ruggiero Courtney H, Jimenez-Rondan Felix R, Morena Francielly, Krassovskaia Polina, Broskey Nicholas T, Sun Yifei, Walsh Martin J, Cousins Robert J, Houmard Joseph A, Sparks Lauren M, Goodpaster Bret H
Аннотация
Skeletal muscle (SkM) insulin resistance is a central defect in T2D, yet cell specific molecular determinants remain incompletely understood. Here, we integrate full-length single-nucleus transcriptomics with gold-standard stable isotope-labeled hyperinsulinemic-euglycemic clamps to generate a nucleus-resolved transcriptomic atlas of SkM insulin resistance. We identify previously unrecognized myonuclear populations whose proportions associate with insulin sensitivity across independent cohorts, revealing MYH7B+ myonuclei are metabolically favorable over EGF+ myonuclei. Modeling transcriptional variation against tracer-derived glucose disposal uncovers highly nucleus-specific molecular programs that are obscured when using surrogate fasting indices. Mechanistically, we identify zinc transporter ZIP14 as a positive regulator of insulin-stimulated glucose uptake and implicate EGF signaling in impaired branched-chain amino acid catabolism and inflammatory cross-talk within the SkM niche. Together, these findings redefine SkM insulin resistance as a multicellular, nucleus-resolved process and highlight new cell type specific targets for metabolic intervention.