Adv Sci (Weinh). 2025 Oct 7:e05989. doi: 10.1002/advs.202505989. Online ahead of print.
ABSTRACT
Exercise triggers molecular changes in skeletal muscles, but distinguishing immediate responses from secondary inter-organ interactions in muscle biopsies remains challenging. Here, this study differentiates human embryonic stem cells (hESCs) into induced skeletal muscle (iMusc) cells to identify hypertrophic factors and generates a novel 3D human iMusc organoid model for studying the direct effects of exercise-like contractions. Transcriptomics profiling reveals iMusc organoids rapidly induced genes associated with calcium signaling, p38/MAPK, EGF/ErbB, and NGF pathways within 1 h, mimicking exercise responses in vivo. Proteomics profiling and in vivo validation reveal rapid activation of both AMPK and mTORC1 signaling, partly through increased Lamtor1 levels, resolving a paradox in exercise biology. Human muscle biopsy analyses reveal Lamtor1 decreases with aging, and increases with exercise. In vivo and organoid experiments both confirm Lamtor1's role in mTORC1-induced strength and AMPK-induced lipid metabolism. Overall, this 3D iMusc organoid model provides insights into primary contraction-induced changes and identifies Lamtor1 as a novel therapeutic target for exercise mimicry.
PMID:41058014 | DOI:10.1002/advs.202505989