Functional primary human 3D skeletal muscle models enable exercise and metabolic research
- 1Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, 72076 Tuebingen, Germany
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-{beta}1 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.
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BibTeX
@misc{dreher2026functional,
title = {{Functional primary human 3D skeletal muscle models enable exercise and metabolic research}},
author = {S. I. Dreher and R. Schoeler and K. S. Zorn and J. Martin and J. Kuehnle and K. Elsner and I. Behle and T. Goj and L. Ruoff and K. Leffek and A. Moruzzi and P. Loskill and A. Tomalka and T. Siebert and A. L. Birkenfeld and A. Peter and C. Weigert},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.29.735246},
url = {https://www.biorxiv.org/content/10.64898/2026.06.29.735246v2},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Functional primary human 3D skeletal muscle models enable exercise and metabolic research
AU - S. I. Dreher
AU - R. Schoeler
AU - K. S. Zorn
AU - J. Martin
AU - J. Kuehnle
AU - K. Elsner
AU - I. Behle
AU - T. Goj
AU - L. Ruoff
AU - K. Leffek
AU - A. Moruzzi
AU - P. Loskill
AU - A. Tomalka
AU - T. Siebert
AU - A. L. Birkenfeld
AU - A. Peter
AU - C. Weigert
PY - 2026
DA - 2026/06/29
PB - bioRxiv
DO - 10.64898/2026.06.29.735246
UR - https://www.biorxiv.org/content/10.64898/2026.06.29.735246v2
AB - 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-{beta}1 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.
ER -