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bioRxiv · 10.64898/2026.02.26.708250

A full-length single nuclei transcriptomic atlas of human skeletal muscle insulin resistance

Whytock, K. L.·Divoux, A.·Vazquez, J.·Hopf, M.·Viggars, M. R.·Gutierrez-Monreal, M. A.·Ruggiero, C. H.·Jimenez-Rondan, F. R.·Morena, F.·Krassovskaia, P.·Broskey, N. T.·Sun, Y.·Walsh, M. J.·Cousins, R. J.·Houmard, J. A.·Sparks, L. M.·Goodpaster, B. H.
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Abstract

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.

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Whytock, K. L., Divoux, A., Vazquez, J., Hopf, M., Viggars, M. R., Gutierrez-Monreal, M. A., Ruggiero, C. H., Jimenez-Rondan, F. R., Morena, F., Krassovskaia, P., Broskey, N. T., Sun, Y., Walsh, M. J., Cousins, R. J., Houmard, J. A., Sparks, L. M., Goodpaster, B. H.. 2026-02-28. A full-length single nuclei transcriptomic atlas of human skeletal muscle insulin resistance. https://doi.org/10.64898/2026.02.26.708250

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