The Immune Landscape of Murine Skeletal Muscle Regeneration and Aging

Abstract

Age-related alterations in the immune system are starting to emerge as key contributors to impairments found in aged organs. A decline in regenerative capacity is a hallmark of tissue aging, however the contribution of immune aging to regenerative failure is just starting to be explored. Here, we applied a strategy combining single-cell RNA-sequencing with flow cytometry and functional assays to perform a complete analysis of the immune environment in the aged regenerating skeletal muscle, with time and single cell resolution. Our results identified previously undescribed immune cell types in the skeletal muscle and revealed an unanticipated complexity and functional heterogeneity in immune populations that have been regarded as homogeneous. Furthermore, we uncovered a profound remodeling of both myeloid and lymphoid compartments in aging. These discoveries challenge established notions on immune regulation of skeletal muscle regeneration, providing a new set of potential targets to improve skeletal muscle health and regenerative capacity in aging.

Note:

Funding Information: This study was supported by funding from Fundação para a Ciência e Tecnologia (PTDC/MED-OUT/8010/2020 and EXPL/MED-OUT/1601/2021) and European Molecular Biology Organization Installation Grant (IG4448). NSS (2022.14294.BD), MB (2020.05627.BD), TC (UI/BD/154081/2022) and IBM (2022.10705.BD) were supported by fellowships from Fundação para a Ciência e Tecnologia. JN (2021.03843.CEECIND) and NLNM (CEECIND/00436/2018) were supported by employment contracts from Fundação para a Ciência e Tecnologia.

Conflict of Interests: The authors declare no competing interests.

Ethical Approval: The experimental protocol was reviewed and approved by iMM ORBEA and licensed by DGAV (project license number 022860\2020).

Keywords: Regeneration, Aging, Skeletal muscle