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Age- and Injury-Associated Human Muscle Stem Cell Senescence Impairs Regenerative Capability Despite Preserved Pool Size
Amanda Tedesco, BS
1; Joanne Kim, BS
2; Tyler Huang, .
3; Tyler R Johnston, MD
2; Ranjan Gupta, MD
4; Michael Hicks, PhD
21University of California, Irvine, School of Medicine, Irvine, CA; 2University of California, Irvine, Irvine, CA; 3University of California Irvine, Irvine, CA; 4University of California Irvine, Orange, CA
INTRODUCTION While there has been much research focused on tendon-to-bone healing with flexor tendon and rotator cuff repair, there has been limited understanding of the changes to the muscle. Animal models have shown an age-related muscle stem cell (MuSC) pool depletion and accumulation of inflammation-induced senescent MuSCs that impair regeneration. Yet, there is limited extrapolation to the human condition and no studies have evaluated human MuSC senescence after tendon injury. MATERIAL & METHODS With IRB approval, supraspinatus muscle biopsies (n=16) were performed at the time of standard-of-care surgery for patients with confirmed tendon tear. Samples were cryosectioned and immunostained to quantify MuSC density (Pax7+DAPI+ MuSCs/100 MF20+ myofibers) as well as the percentage of p16INK4a+ senescent MuSCs. Sections were also stained to quantify myofiber cross-sectional area (CSA) (MF20, laminin), percentage of slow oxidative fibers (Myh7), and fibrosis content (Collagen I/II/III) as a proportion of total area. Statistical analyses comparing variables by Goutallier grade (grade 0-1 vs 2-4) and age (<60 vs 60+ years) were performed using unpaired t-tests on Prism GraphPad with significance level set to p<0.05. RESULTS Patient demographics: mean age 62.5 years (range, 24-79), 31% age <60 years; 44% male; 56% Goutallier grade 0-1. Immunohistologic analysis revealed MuSC pool retention across age and Goutallier grade, but a 12.9-fold increase in the proportion of senescent MuSCs with older age (3.7% vs 47.6%, p=0.009) and 1.9-fold increase with higher Goutallier grade (26.4% vs 50.3%,p=0.0378). Mean myofiber CSA was significantly reduced with both age (7030m2 vs 4147m2, p<0.0001) and Goutallier grade (5822m2 vs 4084m2, p=0.0156), with similar proportions of slow myofibers across all groups. Fibrosis was comparable across Goutallier grades (20.0% vs 17.5%, p=0.6393), but was increased by 2.7-fold in the older group (8.8% vs 23.5%, p=0.0046). CONCLUSIONS Despite MuSC pool preservation in human supraspinatus muscles with higher Goutallier grades, almost half of these cells are senescent and incapable of activation. Furthermore, aging appeared to be an even greater driver of senescence with fibrotic atrophy also more pronounced with aging than with increasing Goutallier grade, while fiber type composition remained stable. These data suggest that age-related MuSC senescence may predispose older adults to fibrofatty atrophy following tendon injury and that the chronic inflammatory state due to injury may induce MuSC aging in younger adults.
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