Summary by Michaela Yuen, PhD (She/Her)

Publication

Human skeletal muscle fibre heterogeneity beyond myosin heavy chains
Nature Communications (DOI: 10.1038/s41467-025-56896-6)

https://pubmed.ncbi.nlm.nih.gov/39971958/

Roger Moreno-Justicia, Thibaux Van der Stede, et al. 

Summary

The intricate diversity of human skeletal muscle fibres has long been reduced to a three-part classification based on myosin heavy chain (MYH) isoforms—type 1 slow-twitch and types 2A and 2X fast-twitch fibres. In a recent study published in Nature Communications, Moreno-Justicia et al. performed single muscle fibre transcriptomics and proteomics at scale – analysing over 1,000 individual fibres from the human vastus lateralis. The study resulted in a compelling redefinition of muscle fibre identity that moves beyond the simplistic MYH fibre type framework.

By sensitive quantification of the three MYH isoforms, the authors observed a surprising discordance between gene expression and protein abundance for the isoform encoding for 2X fibres. The study challenges the existence of pure type 2X fibres in healthy, human skeletal muscle since these could be identified at the RNA, but not the protein level. This finding was strengthened by the fact that 2X fibres at the RNA level were found not to form a clearly distinct group, but rather to blend along a transcriptome-wide continuum with other fast-twitch muscle fibres.

By analysing gene and protein expression profiles, the authors showed that MYH isoforms capture only a fraction of the phenotypic variation that exists among muscle fibres. Differences in metabolic pathways, ribosomal protein abundance, and structural features such as cell junction proteins were found to drive fibre diversity. Additional proteins, non-coding RNAs and microproteins with MYH fibre type specific expression patterns were also identified in this study.

In addition to defining single skeletal muscle fibre characteristics in healthy muscle, the study also investigated fibres from 6 patients with nemaline myopathy, due to genetic variants in ACTA1 and TNNT1. Nemaline myopathy patient muscle fibres exhibited widespread proteomic alterations with a shift towards a fast fibre proteomics signature despite ACTA1-nemaline myopathy muscles showing slow MHC fibre predominance. The authors argue that the observed phenotypic shifts highlight the inadequacy of MYH-based fibre classification and the need for more nuanced molecular definitions, particularly in the study of muscle diseases.

In essence, Moreno-Justicia et al. revealed that the canonical view of muscle fibre types as discrete categories defined by myosin isoforms is outdated. A new, multidimensional model is needed—one grounded in systems biology and empowered by omics technologies—to capture the true complexity of human skeletal muscle. The implications are far-reaching, from refining our understanding of exercise adaptation and ageing to developing targeted interventions for muscle disorders.

About the authors

Roger Moreno Justicia is currently doing his PhD at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen (Denmark, Dr. Atul Deshmukh) and is expected to graduate by the end of 2025. His PhD focuses on the study of human skeletal muscle fiber heterogeneity in the context of exercise and metabolic health using sensitive mass spectrometry-based proteomics.

Thibaux Van der Stede obtained his joint PhD from Ghent University (Belgium, Dr. Wim Derave) and Copenhagen University (Denmark, Dr. Ylva Hellsten) in 2024. His PhD focused on the molecular biology of skeletal muscle in health and disease, with a specific focus on the adaptive response to exercise using various -omics workflows. He is currently working as a postdoctoral researcher on the molecular immunology and inflammation in musculoskeletal diseases at the VIB-UGent Center for Inflammation Research (Dr. Dirk Elewaut).

About the reviewer

Michaela Yuen is a biomedical scientist and muscle physiologist seeking an in-depth understanding of congenital myopathies and other inherited muscle diseases at the University of Sydney, Westmead, Australia. Her work involves disease gene discovery (particularly genetic variants affecting pre-mRNA splicing) and disease pathogenicity studies focusing on the contractile apparatus of skeletal muscle.