Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle
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Abstract
Striated muscle is a highly organized structure composed of well-defined anatomical domains with integrated but distinct assignments. So far, the lack of a direct correlation between tissue architecture and gene expression has limited our understanding of how each unit responds to physio-pathologic contexts. Here, we show how the combined use of spatially resolved transcriptomics and immunofluorescence can bridge this gap by enabling the unbiased identification of such domains and the characterization of their response to external perturbations. Using a spatiotemporal analysis, we follow changes in the transcriptome of specific domains in muscle in a model of denervation. Furthermore, our approach enables us to identify the spatial distribution and nerve dependence of atrophic signaling pathway and polyamine metabolism to glycolytic fibers. Indeed, we demonstrate that perturbations of polyamine pathway can affect muscle function. Our dataset serves as a resource for future studies of the mechanisms underlying skeletal muscle homeostasis and innervation.
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Spatial resolution is critical to determine whether subsarcolemmal nuclei upregulate biogenesis with greater kinetic urgency than intermyofibrillar nuclei or how distinct functional clusters locally upregulate their ribogenic response.
“This spatial resolution is critical to determine whether subsarcolemmal nuclei upregulate biogenesis with greater kinetic urgency than intermyofibrillar nuclei, or how distinct functional clusters (such as specific innervation-responsive zones) locally upregulate their ribogenic response, thereby adding a crucial topological dimension to the bottleneck theory [81,82].”
From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [81]
The Discussion describes spatial and temporal transcriptional responses in distinct muscle domains after nerve damage, supporting the value of spatial resolution for studying innervation-responsive clusters. It does not compare subsarcolemmal with intermyofibrillar nuclei or report local ribogenic responses; the Limitations of the study also state that spot-level expression averages multiple cells. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSpatial transcriptomics can map mRNA and pre-rRNA transcripts directly onto intact histological sections.
“advanced Q1 methodology is increasingly deploying spatial transcriptomics (e.g., visium or slide-seq) to map mRNA and pre-rRNA transcripts directly onto intact histological sections [81,82].”
From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [81]
The section “Spatial transcriptome analysis identifies eight different clusters in muscle tissue” describes placing stained muscle cryosections on Visium slides and mapping captured polyadenylated RNA to its histological location. This supports spatial mapping of mRNA in tissue sections, but the paper does not report mapping pre-rRNA transcripts. No page number is available in our copy. (LLM, conf=0.88)
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“…nuclei upregulate biogenesis with greater kinetic urgency than intermyofibrillar nuclei, or how distinct functional clusters (such as specific innervation-responsive zones) locally upregulate their ribogenic response, thereby adding a crucial topological dimension to the bottleneck theory [81,82].”
- Authors
- D’Ercole, C., D’Angelo, P., Ruggieri, V., Proietti, D., Virtanen, L., Parisi, C., Riera, C. S., Renzini, A., Macone, A., Marzullo, M., Ciapponi, L., Bonvissuto, D., Sette, C., Giordani, L., & Madaro, L.
- Affiliations
- Istituto Pasteur (IT)
- IRCCS Ospedale San Raffaele (IT)
- Inserm (FR)
- Sapienza University of Rome (IT)
- Institute of Molecular Biology and Pathology (IT)
- Università Cattolica del Sacro Cuore (IT)
- Corresponding author
- Giordani, Lorenzo
- Madaro, Luca
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 41
- Issue
- 12
- Pages
- 111861
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W4312084962
- Cited by
- 48
- References
- 60
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 12 · 2023: 11
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by)
- HAL (submittedVersion)
- Funders
- Istituto Pasteur-Fondazione Cenci Bolognetti
- AFM-Téléthon (23075)
- Agence Nationale de la Recherche (ANR-20-CE14-0048)
- Institut Pasteur
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- skeletal muscle, muscle innervation, denervation, muscle atrophy, polyamine metabolism, glycolytic fibers, muscle fiber type, spatial transcriptomics, muscle homeostasis
- MeSH terms
- Humans, Muscular Atrophy, Polyamines, Muscle, Skeletal, Gene Expression Profiling, Transcriptome
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