Research Paper Volume 15, Issue 10 pp 4035—4050

Changes in macrophage immunometabolism as a marker of skeletal muscle dysfunction across the lifespan

Norika Liu1,2, , Joshua T. Butcher3, , Atsushi Nakano1,2,4, , Andrea del Campo5, ,

  • 1 Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan
  • 2 Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
  • 3 Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
  • 4 David Geffen Department of Medicine, Division of Cardiology, University of California Los Angeles, Los Angeles, CA 90095, USA
  • 5 Laboratorio de Fisiología y Bioenergetica Celular, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7810000, Chile

Received: March 1, 2023       Accepted: May 16, 2023       Published: May 25, 2023
How to Cite

Copyright: © 2023 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


One of the most pronounced changes in the elderly is loss of strength and mobility due to the decline of skeletal muscle function, resulting in a multifactorial condition termed sarcopenia. Although significant clinical changes begin to manifest at advanced ages, recent studies have shown that changes at the cellular and molecular level precede the symptomatology of sarcopenia. By utilizing a single-cell transcriptomic atlas of mouse skeletal muscle across the lifespan, we identified a clear sign of immune senescence that presents during middle age. More importantly, the change in macrophage phenotype in middle age may explain the changes in extracellular matrix composition, especially collagen synthesis, that contributes to fibrosis and overall muscle weakness with advanced age. Our results show a novel paradigm whereby skeletal muscle dysfunction is driven by alterations in tissue-resident macrophages before the appearance of clinical symptoms in middle-aged mice, providing a new therapeutic approach via regulation of immunometabolism.


TRM: Tissue-resident macrophage; EMP: erythromyeloid progenitor cell; scRNA-sequence: single cell RNA sequence; GO: gene ontology; DEG: differentially expressed gene; ECM: extracellular matrix; NMJ: neuromuscular junction; GEO: Gene Expression Omnibus.