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Myofiber-specific pathological programs in mTORC1-driven myopathy

ABSTRACT: Skeletal muscle contains diverse myofiber types and non-myocyte populations, but the molecular basis of many myopathies remains poorly defined because conventional methods cannot directly connect histopathology with gene expression at single-fiber resolution. We applied high-resolution Seq-Scope spatial transcriptomics to extensor digitorum longus and soleus muscles from a mouse model of mTORC1 hyperactivation. The analysis revealed fiber-type-specific pathological responses. Type I and IIa fibers showed limited morphological changes, whereas type IIx fibers followed distinct trajectories. In soleus, type IIx fibers exhibited abnormal enlargement associated with growth signaling, cytoskeletal remodeling, and impaired proteostasis. In extensor digitorum longus, type IIx fibers developed basophilia associated with increased RNA content and transcriptional signatures related to lipid, oxidative, and nucleotide metabolism. Type IIb fibers also displayed multiple transcriptional states. Macrophages and fibroblasts preferentially accumulated in soleus, where they contributed to an inflammatory and fibrotic microenvironment. These data link muscle histopathology with spatially resolved molecular states at single-fiber resolution.

ORGANISM(S): Mus musculus

PROVIDER: GSE338936 | GEO | 2026/07/26

REPOSITORIES: GEO

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