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.
Show 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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- The mitochondrial mRNA stabilizing protein, SLIRP, regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms 96%
- Training-induced bioenergetic improvement in human skeletal muscle is associated with non-stoichiometric changes in the mitochondrial proteome without reorganization of respiratory chain content 96%
- Transcriptomic Profiling of Skeletal Muscle Adaptations to Exercise and Inactivity 96%
Similar papers in this journal
- MME+ fibro-adipogenic progenitors are the dominant adipogenic population during fatty infiltration in human skeletal muscle 96%
- Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis 95%
- Revealing grand-paternal programming of lipid metabolism using a novel computational tool 94%
Similar papers in this journal
- Chemical inhibition of SUMOylation activates the FSHD locus 94%
- Identification of new interactors of eIF3f by endogenous proximity-dependent biotin labelling in human muscle cells. 94%
- Synteny: a high throughput web tool to streamline causal gene prioritisation and provide insight into protein function 94%
Similar papers in this journal
- Molecular profiling of high-level athlete skeletal muscle after acute exercise - a systems biology approach 95%
- Leukocyte-type 12/15-lipoxygenase is essential for timely inflammation-resolution and effective tissue regeneration following skeletal muscle injury 94%
- HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis 94%
Similar papers in this journal
- Caloric restriction reprograms adipose tissues in rhesus monkeys 95%
- Higher Expression of Denervation-responsive Genes is Negatively Associated with Muscle Volume and Performance Traits in the Study of Muscle, Mobility and Aging (SOMMA) 94%
- Metabolic and age-associated epigenetic barriers during direct reprogramming of mouse fibroblasts into induced cardiomyocytes 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.