Mechanisms of impaired muscle repair following influenza infection in aged mice.

Older adults are susceptible to infectious diseases including Influenza (flu), due to widely accepted declines in immune response with age. Flu infection in older adults commonly results in hospitalization and catastrophic disability, leading to loss of independence. Previous findings demonstrate that flu infection induces severe and prolonged muscle injury in aged mice. We aimed to explore the effects of flu infection on skeletal muscle gene expression and immune cell populations to elucidate mechanisms of flu-induced disability in older adults. Young and aged C57BL/6 male mice were infected with a sublethal dose of PR8 (H1N1) influenza. Gastrocnemius muscles were harvested for RNA sequencing, confocal microscopy, and flow cytometry. Our findings showed differential gene expression changes between young and aged mice, including downregulation of muscle regeneration and organization genes and upregulation proinflammatory cytokine and migratory cell pathways in aged muscle. Pathway analysis revealed significant increases in T cell activation pathways in the aged muscle. Confocal microcopy confirmed increased leukocytes (CD45+) and T cells (CD3+) intramuscularly following flu infection. Flow cytometric analyses confirmed that aged mice have increased infiltrating CD8 T cells during infection compared to young mice, while young muscle have increased infiltrating regulatory T cells (Tregs) compared to their aged counterparts. Further analysis suggested that differences in IL-33 levels between young and aged mice influence these infiltrating populations. Future research is necessary to determine if IL-33 supplementation may prevent or ameliorate flu-induced disability in older adults.

Supported by NIH/NIA R01 AG051647 (Co-I) NIH/NIA R01 AR075346 (Co-I) NIH/NIA R33 AG061456 (Co-I) NIH/NIA R21 AG071292 (Co-I) American Federation for Aging Research Reboot (PI)