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However, the underlying mechanism is still unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The differentiated expressed genes in young and aged muscles after acute injury by cardiotoxin were identified by RNA\u2010sequence analysis. Single\u2010cell RNA\u2010sequence analysis was used to identify cell clusters and functions in young muscle after acute injury, and flow cytometry analysis and sorting were used to validate the function. The proliferation and differentiation functions of satellite cells were accessed by immunostaining with 5\u2010ethynyl\u20102\u2032\u2010deoxyuridine and embryonic myosin heavy chain (eMyHC), respectively. Muscle regeneration ability was accessed by histopathological and molecular biological methods.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Gene expression patterns associated with responses to interferon\u2010gamma (IFN\u2010\u03b3) (15 genes; false discovery rate\u00a0&lt;\u00a00.001) were significantly down\u2010regulated during muscle regeneration in aged mice (<jats:italic>P<\/jats:italic>\u00a0=\u00a02.25e\u22127). CD8<jats:sup>+<\/jats:sup> T cells were the main source of increased IFN\u2010\u03b3 after injury, adoptive transfer of wild\u2010type CD8<jats:sup>+<\/jats:sup> T cells to IFN\u2010\u03b3\u2010deficient young mice resulted in 78% increase in cross\u2010sectional areas (CSAs) of regenerated myofibres (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and 63% decrease in muscle fibrosis (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) after injury. Single\u2010cell RNA\u2010sequence analysis identified a novel subset of macrophages [named as IFN\u2010responsive macrophages (IFNRMs)] that specifically expressed IFN\u2010responsive genes (<jats:italic>Ifit3<\/jats:italic>, <jats:italic>Isg15<\/jats:italic>, <jats:italic>Irf7<\/jats:italic>, etc.) in young mice at 3\u00a0days after injury, and the number of this macrophage subset was ~20% lower in aged mice at the same time (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). IFNRMs secreted cytokine C\u2010X\u2010C motif chemokine 10 (CXCL10) that promoted the proliferation and differentiation of satellite cells via its receptor, CXCR3. Intramuscular recombinant CXCL10 treatment in aged mice rejuvenated the proliferation of satellite cells (80% increase in Ki\u201067<jats:sup>+<\/jats:sup>Pax7<jats:sup>+<\/jats:sup> cells, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and resulted in 27% increase in CSA of regenerated myofibres (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and 29% decrease in muscle fibrosis (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study indicates that decline in IFN\u2010\u03b3 response in a novel subset of macrophage contributes to satellite cells dysfunctions in aged skeletal muscles and demonstrates that this mechanism can be targeted to restore age\u2010associated myogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12584","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T07:12:50Z","timestamp":1596006770000},"page":"1291-1305","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Age\u2010related decline of interferon\u2010gamma responses in macrophage impairs satellite cell proliferation and regeneration"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4932-3412","authenticated-orcid":false,"given":"Congcong","family":"Zhang","sequence":"first","affiliation":[{"name":"Beijing Anzhen Hospital Capital Medical University; Key Laboratory of Remodeling\u2010related Cardiovascular Diseases, Ministry of Education; Beijing Collaborative Innovation Center for Cardiovascular Disorders; Beijing Institute of Heart, Lung and Blood Vessel Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naixuan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Beijing Anzhen Hospital Capital Medical University; Key Laboratory of Remodeling\u2010related Cardiovascular Diseases, Ministry of Education; Beijing Collaborative Innovation Center for Cardiovascular Disorders; Beijing Institute of Heart, Lung and Blood Vessel Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bokang","family":"Qiao","sequence":"additional","affiliation":[{"name":"Beijing Anzhen Hospital Capital Medical University; Key Laboratory of Remodeling\u2010related Cardiovascular Diseases, Ministry of Education; Beijing Collaborative Innovation Center for Cardiovascular Disorders; Beijing Institute of Heart, Lung and Blood Vessel Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Anzhen Hospital Capital Medical University; Key Laboratory of Remodeling\u2010related Cardiovascular Diseases, Ministry of Education; Beijing Collaborative Innovation Center for Cardiovascular Disorders; Beijing Institute of Heart, Lung and Blood Vessel Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wu","sequence":"additional","affiliation":[{"name":"Section of Physiology and Biochemistry of Sports Capital University of Physical Education and Sports  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Anzhen Hospital Capital Medical University; Key Laboratory of Remodeling\u2010related Cardiovascular Diseases, Ministry of Education; Beijing Collaborative Innovation Center for Cardiovascular Disorders; Beijing Institute of Heart, Lung and Blood Vessel Diseases  Beijing 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