Aging disrupts gene expression timing during muscle regeneration

Jesse V Kurland; Alicia A Cutler; Jacob T Stanley; Nicole Dalla Betta; Ashleigh Van Deusen; Brad Pawlikowski; Monica Hall; Tiffany Antwine; Alan Russell; Mary Ann Allen; Robin Dowell; Bradley Olwin

doi:10.1016/j.stemcr.2023.05.005

Aging disrupts gene expression timing during muscle regeneration

Stem Cell Reports. 2023 Jun 13;18(6):1325-1339. doi: 10.1016/j.stemcr.2023.05.005.

Authors

Affiliations

¹ Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
² BioFrontiers Institute, University of Colorado, Boulder, 3415 Colorado Avenue, Boulder, CO 80303, USA.
³ Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA; Edgewise Therapeutics, 3415 Colorado Avenue, Boulder, CO 80303, USA.
⁴ Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA; Department of Pediatrics Section of Section of Hematology, Oncology, Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
⁵ Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA; Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59718, USA.
⁶ Edgewise Therapeutics, 3415 Colorado Avenue, Boulder, CO 80303, USA.
⁷ Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA; BioFrontiers Institute, University of Colorado, Boulder, 3415 Colorado Avenue, Boulder, CO 80303, USA. Electronic address: robin.dowell@colorado.edu.
⁸ Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA. Electronic address: olwin@colorado.edu.

Abstract

Skeletal muscle function and regenerative capacity decline during aging, yet factors driving these changes are incompletely understood. Muscle regeneration requires temporally coordinated transcriptional programs to drive myogenic stem cells to activate, proliferate, fuse to form myofibers, and to mature as myonuclei, restoring muscle function after injury. We assessed global changes in myogenic transcription programs distinguishing muscle regeneration in aged mice from young mice by comparing pseudotime trajectories from single-nucleus RNA sequencing of myogenic nuclei. Aging-specific differences in coordinating myogenic transcription programs necessary for restoring muscle function occur following muscle injury, likely contributing to compromised regeneration in aged mice. Differences in pseudotime alignment of myogenic nuclei when comparing aged with young mice via dynamic time warping revealed pseudotemporal differences becoming progressively more severe as regeneration proceeds. Disruptions in timing of myogenic gene expression programs may contribute to incomplete skeletal muscle regeneration and declines in muscle function as organisms age.

Keywords: MuSC; aging; cell fate; differentiation; myonuclei; pseudotime; regeneration; single-nucleus RNA sequencing; skeletal muscle regeneration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics
Animals
Cell Nucleus*
Gene Expression
Mice
Muscle, Skeletal
Stem Cells*