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Myopathies occur in many diseases, but the mechanisms driving these pathologies remain largely unknown, partly because conventional approaches cannot link histopathological features to molecular states at single-fiber resolution. To address this challenge, we brought histopathology and spatial transcriptomics together by applying high-resolution Seq-Scope technology to a mouse model of mTORC1 hyperactivation. Cross-sections from the extensor digitorum longus (EDL) and soleus (SOL), two muscles with distinct fiber-type compositions, were profiled to determine how transcriptome changes are linked to histopathological outcomes. mTORC1 hyperactivation elicited distinct, fiber type\u2013dependent pathological programs. Type I and IIa fibers were largely resistant to mTORC1-induced pathology, exhibiting relatively limited morphological alterations. In contrast, type IIx fibers diverged into opposing fates: in SOL, they underwent abnormal enlargement associated with sustained growth signaling, cytoskeletal remodeling, and impaired proteostasis; in EDL, they developed basophilia associated with increased RNA content and lipid-, oxidative-, and nucleotide metabolism\u2013related signatures. Within EDL, type IIb fibers displayed heterogeneity with discrete transcriptional states. Non-myocytic populations, including macrophages and fibroblasts, accumulated preferentially in SOL, forming a fibrotic microenvironment associated with inflammation, remodeling, and hypertrophy. These findings provide a link between histopathological phenotypes and molecular states at single-fiber resolution.<\/jats:p>","DOI":"10.1172\/jci.insight.203167","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:01:31Z","timestamp":1787241691000},"source":"Crossref","is-referenced-by-count":0,"title":["Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy"],"prefix":"10.1172","volume":"11","author":[{"given":"Jer-En","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Molecular & Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Molecular & Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqiu","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Min","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1954-967X","authenticated-orcid":true,"given":"Susan V.","family":"Brooks","sequence":"additional","affiliation":[{"name":"Department of Molecular & Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myungjin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular & Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular & Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2010"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0029(20000915)50:6<500::AID-JEMT7>3.0.CO;2-7"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3025"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2763"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1232044"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2021.2016255"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.005970"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.03.015"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2152"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2017.02.004"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.10.024"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.12703\/r\/11-32"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.10.002"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-019-0131-9"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-024-00613-3"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-024-00756-3"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20063-w"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-020-00236-3"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.100993"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.02.067"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-57110-6"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03938-0"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.02.026"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.04.017"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.105415"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-57487-1"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1101\/gr.278717.123"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18789-8"},{"key":"B29","doi-asserted-by":"crossref","unstructured":"Wang YX, et al. 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