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ResearchIn-Press PreviewCell biologyMuscle biology Open Access | 10.1172/jci.insight.203167

Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy

Jer-En Hsu,1 Qingyang Zhao,1 Weiqiu Cheng,2 Hyun Min Kang,2 Susan V. Brooks,1 Myungjin Kim,1 and Jun Hee Lee1

1Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States of America

2Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

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1Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States of America

2Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Zhao, Q. in: PubMed | Google Scholar

1Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States of America

2Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Cheng, W. in: PubMed | Google Scholar

1Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States of America

2Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Kang, H. in: PubMed | Google Scholar

1Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States of America

2Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Brooks, S. in: PubMed | Google Scholar |

1Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States of America

2Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Kim, M. in: PubMed | Google Scholar

1Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States of America

2Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Lee, J. in: PubMed | Google Scholar

Published August 20, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.203167.
Copyright © 2026, Hsu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 20, 2026 - Version history
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Abstract

Skeletal muscle is composed of heterogeneous myofiber types and non-myocyte populations. Myopathies occur in many diseases, but 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 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-dependent 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-related 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.

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