Cellular signaling within aged skeletal muscle reveals a dysregulated stress-induced remodeling response following volumetric muscle loss in female mice

Authors
Krista M. Habing, Tyler J. Sagendorf, Cynthia A. Alcazar-Daleo, James A. Sanford, Damon Leach, Joshua C. Vanderpool, Chelsea M. Hutchinson-Bunch, Marina Gritsenko, Gina M. Many, Karina H. Nakayama


Lab

Journal
Physiological Reports

Abstract
Building on this differential analysis, pathway-level enrichment was performed using reference Reactome and Gene Ontology Biological Processes (GOBP) gene set curations. When comparing the injured muscle in aged versus young mice, enrichment of classical antibody mediated complement activation (z= 7.67,p= 1.19E-11) and related immune pathways (e.g., Fc-gamma receptor activation and CD22-mediated B-cell receptor regulation) was noted in aged animals and enrichment of translation and mRNA surveillance pathways was noted in young animals. In aged mice, injured muscles showed significant downregulation of several metabolic pathways relative to uninjured controls (e.g., mitochondrial respiratory chain complex assembly,z= −5.28,p= 0.00014), whereas no comparable suppression was detected in young mice. Across both ages, injury persistently enriched extracellular (e.g., extracellular structure organization,z= 3.91–5.23,p= 0.00014–0.000958), cytoskeletal (e.g., regulation of actin nucleation,z= 4.33–4.69,p= 0.0011–0.0027), and nuclear remodeling pathways, as well as immune surveillance and antigen handling (e.g., phagocytosis,z= 4.96–5.65,p= 0.00022–2.92E-5), indicating persistent structural and immune activity even at 28 days post-injury (Figure6band TableS3). Pathway enrichment analysis utilizing the CellMarker (Hu et al.,2023) database, which is curated to murine cellular populations, further confirmed sustained immune involvement following VML injury in both young and aged mice. Enrichment was particularly observed among macrophage and monocyte populations (p< 0.05, FigureS2A). The Pathway Interaction Database (Schaefer et al.,2009) also identified age- and injury-associated differences in adhesion-related pathways, including integrin β1/β3 signaling and adherens junction stability. Class II histone deacetylase-associated signatures (HDACs), regulators of myogenic gene expression, showed contrasting patterns in the PID dataset, with reduced representation in uninjured muscles from aged versus young mice (z= −4.03,p= 0.0097) and increased representation in injured versus uninjured muscle from aged mice (z= 3.34,p= 0.022, FigureS2Band TableS3). Given the reported roles of HDACs in muscle aging and injury responses (Spallotta et al.,2013; Walsh & van Remmen,2016), these patterns may reflect age-dependent shifts in the regulation of regenerative transcriptional programs. These findings suggest that, despite minimal differential protein abundance 28 days post-injury, age and injury continue to influence immune, metabolic, and structural processes relevant to longer-term muscle recovery.

Keywords/Topics
aging; inflammation; muscle regeneration; phosphoproteomics; stress response; volumetric muscle loss

Source :

https://physoc.onlinelibrary.wiley.com/doi/abs/10.14814/phy2.71022

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