Human skeletal muscle fiber heterogeneity beyond myosin heavy chains

Roger Moreno-Justicia, Thibaux Van der Stede, Ben Stocks, Jenni Laitila, Robert A. Seaborne, Alexia Van de Loock, Eline Lievens, Diana Samodova, Leyre Marín-Arraiza, Oksana Dmytriyeva, Robin Browaeys, Kim Van Vossel, Lukas Moesgaard, Nurten Yigit, Jasper Anckaert, Anneleen Weyns, Ruud Van Thienen, Ronni E. Sahl, Edmar Zanoteli, Michael W. Lawlor, Michael Wierer, Pieter Mestdagh, Jo Vandesompele, Julien Ochala, Morten Hostrup, Wim Derave () and Atul S. Deshmukh ()
Additional contact information
Roger Moreno-Justicia: University of Copenhagen
Thibaux Van der Stede: Ghent University
Ben Stocks: University of Copenhagen
Jenni Laitila: University of Copenhagen
Robert A. Seaborne: University of Copenhagen
Alexia Van de Loock: Ghent University
Eline Lievens: Ghent University
Diana Samodova: University of Copenhagen
Leyre Marín-Arraiza: University of Copenhagen
Oksana Dmytriyeva: University of Copenhagen
Robin Browaeys: VIB Center for Inflammation Research
Kim Van Vossel: Ghent University
Lukas Moesgaard: University of Copenhagen
Nurten Yigit: Ghent University
Jasper Anckaert: Ghent University
Anneleen Weyns: Ghent University
Ruud Van Thienen: Ghent University
Ronni E. Sahl: University of Copenhagen
Edmar Zanoteli: Universidade de São Paulo
Michael W. Lawlor: Medical College of Wisconsin
Michael Wierer: University of Copenhagen
Pieter Mestdagh: Ghent University
Jo Vandesompele: Ghent University
Julien Ochala: University of Copenhagen
Morten Hostrup: University of Copenhagen
Wim Derave: Ghent University
Atul S. Deshmukh: University of Copenhagen

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Skeletal muscle is a heterogenous tissue comprised primarily of myofibers, commonly classified into three fiber types in humans: one “slow” (type 1) and two “fast” (type 2A and type 2X). However, heterogeneity between and within traditional fiber types remains underexplored. We applied transcriptomic and proteomic workflows to 1050 and 1038 single myofibers from human vastus lateralis, respectively. Proteomics was conducted in males, while transcriptomics included ten males and two females. We identify metabolic, ribosomal, and cell junction proteins, in addition to myosin heavy chain isoforms, as sources of multi-dimensional variation between myofibers. Furthermore, whilst slow and fast fiber clusters are identified, our data suggests that type 2X fibers are not phenotypically distinct to other fast fibers. Moreover, myosin heavy chain-based classifications do not adequately describe the phenotype of myofibers in nemaline myopathy. Overall, our data indicates that myofiber heterogeneity is multi-dimensional with sources of variation beyond myosin heavy chain isoforms.

Date: 2025
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DOI: 10.1038/s41467-025-56896-6

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