Functional primary human 3D skeletal muscle models enable exercise and metabolic research

作者：Simon I. Dreher, Robin Schoeler, Katharina S. Zorn, Jens Martin, Jana Kuehnle, Kevin Elsner, I Behle, Thomas Goj, Lara Ruoff, Kolja Leffek, Alessia Moruzzi, Peter Loskill, André Tomalka, Tobias Siebert, Andreas L. Birkenfeld, Andreas Peter, Cora Weigert · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.06.29.735246 · 研究领域：Adipose Tissue and Metabolism、Muscle Physiology and Disorders、Metabolism, Diabetes, and Cancer

Abstract Human skeletal muscle is the principal site of insulin-stimulated glucose disposal and a major mediator of exercise-induced metabolic benefits, yet human models that preserve metabolic and exercise responsiveness remain limited. We generated primary human skeletal muscle organoids from donor-derived CD56+ myoblasts using a collagen-based extracellular matrix and serum-free IGF1-guided differentiation. The organoids formed aligned contractile tissues containing oxidative and glycolytic fiber type-like myotubes, displayed enhanced mitochondrial respiration, insulin-stimulated glucose uptake, and reproducible force generation. Electrical pulse stimulation induced AMPK activation, increased glucose utilization and lactate production, and upregulated canonical exercise-responsive genes including NR4A3 and PPARGC1A . Notably, transcriptional responses to in vitro exercise overlapped with acute exercise responses observed in skeletal muscle biopsies from the same donors. The organoids further detected functional impairments of skeletal muscle performance induced by TGF-β1 and metformin and increased speed generation by testosterone treatment. These findings establish a donor-specific human skeletal muscle platform that recapitulates key features of insulin action and exercise adaptation and may enable mechanistic studies of skeletal muscle metabolism, exercise responsiveness, and therapeutic interventions relevant to diabetes. Graphical Abstract Article highlights We genera...