Muscle Organoids Reveal Exercise‐Like Contractions Rapidly Promote Muscle Health Via Lamtor1's Signaling to Both AMPK and mTOR

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.