Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy
- 1Department of Molecular & Integrative Physiology and
- 2Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Abstract
Skeletal muscle is composed of heterogeneous myofiber types and non-myocyte populations. 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–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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BibTeX
@article{hsu2026histopathology,
title = {{Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy}},
author = {Jer-En Hsu and Qingyang Zhao and Weiqiu Cheng and Hyun Min Kang and Susan V. Brooks and Myungjin Kim and Jun Hee Lee},
journal = {JCI Insight},
year = {2026},
month = aug,
doi = {10.1172/jci.insight.203167},
url = {https://doi.org/10.1172/jci.insight.203167},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy
AU - Jer-En Hsu
AU - Qingyang Zhao
AU - Weiqiu Cheng
AU - Hyun Min Kang
AU - Susan V. Brooks
AU - Myungjin Kim
AU - Jun Hee Lee
PY - 2026
DA - 2026/08/20
JO - JCI Insight
DO - 10.1172/jci.insight.203167
UR - https://doi.org/10.1172/jci.insight.203167
AB - Skeletal muscle is composed of heterogeneous myofiber types and non-myocyte populations. 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–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.
SN - 2379-3708
ER -