Delineating the relationship between immune system aging and myogenesis in muscle repair

Abstract

12How aging affects the communication between immune cells and myoblasts during myogenesis 13 is unclear. We therefore investigated how aging impacts the cellular synchronization of these two 14 processes after muscle injury. Muscles of old mice (20 months) had chronic inflammation and 15 fewer satellite cells compared to young mice (3 months). After injury, young mice developed a 16 robust, but transient inflammatory response and a stepwise myogenic gene expression program. 17 These responses were impaired with age. Replacement of old bone marrow (BM) via 18 heterochronic bone marrow transplantation (BMT) increased muscle mass and performance on 19 locomotive and behavioural tests. After injury, Y-O BMT restored the immune cell and cytokine 20 profiles to a young phenotype and enhanced satellite cell activity while O-O BMT amplified a 21late-onset proinflammatory response. In vitro, conditioned media from young or old 22 macrophages had no effect or impaired myoblast proliferation, respectively. Thus, BM age 23 negatively affects myogenesis by inhibiting myoblast proliferation. 24 25 26 29proliferate and differentiate into mature muscle. The satellite cell population is limited, however, 30 as extensive activation caused by chronic injury may exhaust the stem cell pool 1 . Aging also 31 results in homeostatic and regenerative defects that leads to muscle loss via signals that are both 32 intrinsic and extrinsic to the satellite cell 2 . These signals ultimately impact absolute progenitor 33 cell number and function. 34Satellite cells become inherently defective with age, as transplantation of old satellite 35 cells to young muscle fail to repair muscle effectively 3,4 . Intrinsic factors that may account for 36 satellite cell aging include increased DNA damage, increased expression of cell cycle checkpoint 37 regulators such as p16 and p53, and loss of H3K27me3 histone methylation via reduced Ezh2 38 activity 5-7 . Aged muscle is subject to higher levels of muscle turnover by changes in the satellite 39 cell niche which may exhaust the stem cell pool 8 . With age, satellite cells also become prone to 40 higher levels of symmetric division, leading to fewer Pax7 + progenitor cells 4 , and geriatric 41 satellite cells may also enter an irreversible state of quiescence 7 . Myogenesis may also be 42 influenced by extrinsic factors in the blood that differ with age. This has been documented using 43 heterochronic parabiosis and blood transfusion 9-11 . Circulating factors, particularly members of 44 the TGF-β superfamily, increase with age and contribute to muscle wasting via upregulation of 45 cyclin dependent kinase inhibitors 12 . Despite moderate improvements in aged mice that receive 46 young blood 11 , the aged muscle microenvironment limits regenerative capacity. 47In addition to satellite cells, there are muscle-resident cells such as macrophages, 48 endothelial cells, Hoechst dye-excluding Side Population cells, and mesenchymal stem cells. 49Some of these cells arise from circulating cells which originate f...

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

“…Heterochronic (young to old) bone marrow transplant in 20-22 month old mice improves angiogenesis via upregulation of Cxcl12, Vegf and the inflammatory response post-MI [172,174,208]. Young bone marrow cell transplantation can also improve cognitive function and muscle repair in aged mice, implying a greater scope for bone marrow cell aging on systemic tissue aging [209][210][211]. Of note, cognitive improvements in old mice with young bone marrow is caused by changes in both neurons and microglia, the immune cell population in the brain [209,212].…”