Twist2-expressing cells reside in human skeletal muscle and are responsive to aging and resistance exercise training

Nick Gaulton, Griffen Wakelin, Laura V Young, Scott Wotherspoon, Michael Kamal, Gianni Parise, Joshua P Nederveen, Andy Holwerda, Lex B Verdijk, Luc J C van Loon, Tim Snijders, Adam P Johnston*

*Corresponding author for this work

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Skeletal muscle is maintained and repaired by sub-laminar, Pax7-expressing satellite cells. However, recent mouse investigations have described a second myogenic progenitor population that resides within the myofiber interstitium and expresses the transcription factor Twist2. Twist2-expressing cells exclusively repair and maintain type IIx/b muscle fibers. Currently, it is unknown if Twist2-expressing cells are present in human skeletal muscle and if they function as myogenic progenitors. Here, we perform a combination of single-cell RNA sequencing analysis and immunofluorescence staining to demonstrate the identity and localization of Twist2-expressing cells in human skeletal muscle. Twist2-expressing cells were identified to be anatomically and transcriptionally comparable to fibro-adipogenic progenitors (FAPs) and lack expression of typical satellite cell markers such as Pax7. Comparative analysis revealed that human and mouse Twist2-expressing cells were highly transcriptionally analogous and resided within the same anatomical structures in vivo. Examination of young and aged skeletal muscle biopsy samples revealed that Twist2-positive cells are more prevalent in aged muscle and increase following 12-weeks of resistance exercise training (RET) in humans. However, the quantity of Twist2-positive cells was not correlated with indices of muscle mass or muscle fiber cross-sectional area (CSA) in young or older muscle, and their abundance was surprisingly, negatively correlated with CSA and myonuclear domain size following RET. Taken together, we have identified cells expressing Twist2 in human skeletal muscle which are responsive to aging and exercise. Further examination of their myogenic potential is warranted.

Original languageEnglish
Pages (from-to)e22642
Number of pages15
JournalFaseb Journal
Issue number12
Publication statusPublished - Dec 2022


  • Humans
  • Mice
  • Animals
  • Aged
  • Resistance Training
  • Muscle, Skeletal/metabolism
  • Muscle Fibers, Skeletal/metabolism
  • Muscle Development
  • Aging
  • Satellite Cells, Skeletal Muscle/metabolism
  • Repressor Proteins/metabolism
  • Twist-Related Protein 1/genetics

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