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So far, exercise provides the only means to counteract age\u2010related decrements in physical performance and muscle function. Unfortunately, the effectiveness of exercise interventions in elderly populations is hampered by reduced acceptance and compliance as well as disuse complications. We therefore studied whether application of interleukin\u20106 (IL\u20106), a pleiotropic myokine that is induced by skeletal muscle activity and exerts broad systemic effects in response to exercise, affects physical performance and muscle function alone or in combination with training in aged mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sedentary old male mice (Sed+Saline, <jats:italic>n<\/jats:italic>\u00a0=\u00a015) were compared with animals that received recombinant IL\u20106 (rIL\u20106) in an exercise\u2010mimicking pulsatile manner (Sed+IL\u20106, <jats:italic>n<\/jats:italic>\u00a0=\u00a016), were trained with a moderate\u2010intensity, low\u2010volume endurance exercise regimen (Ex+Saline, <jats:italic>n<\/jats:italic>\u00a0=\u00a013), or were exposed to a combination of these two interventions (Ex+IL\u20106, <jats:italic>n<\/jats:italic>\u00a0=\u00a016) for 12\u00a0weeks. Before and at the end of the intervention, mice underwent a battery of tests to quantify endurance performance, muscle contractility <jats:italic>in situ<\/jats:italic>, motor coordination, and gait and metabolic parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mice exposed to enhanced levels of IL\u20106 during endurance exercise bouts showed superior improvements in endurance performance (33% more work and 12% greater peak power compared with baseline), fatigue resistance <jats:italic>in situ<\/jats:italic> (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0014 <jats:italic>vs<\/jats:italic>. Sed+Saline; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0199 <jats:italic>vs<\/jats:italic>. Sed+IL\u20106; and <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0342 <jats:italic>vs<\/jats:italic>. Ex+Saline), motor coordination (rotarod performance, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0428), and gait (gait speed, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0053) following training. Pulsatile rIL\u20106 treatment in sedentary mice had only marginal effects on glucose tolerance and some gait parameters. No increase in adverse events or mortality related to rIL\u20106 treatment was observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Administration of rIL\u20106 paired with treadmill running bouts potentiates the adaptive response to a moderate\u2010intensity low\u2010volume endurance exercise regimen in old mice, while being safe and well tolerated.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12949","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T09:40:21Z","timestamp":1645522821000},"page":"1164-1176","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Interleukin\u20106 potentiates endurance training adaptation and improves functional capacity in old mice"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5800-005X","authenticated-orcid":false,"given":"Aurel B.","family":"Leuchtmann","sequence":"first","affiliation":[{"name":"Biozentrum University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1732-1110","authenticated-orcid":false,"given":"Regula","family":"Furrer","sequence":"additional","affiliation":[{"name":"Biozentrum University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan A.","family":"Steurer","sequence":"additional","affiliation":[{"name":"Biozentrum University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8158-9424","authenticated-orcid":false,"given":"Konstantin","family":"Schneider\u2010Heieck","sequence":"additional","affiliation":[{"name":"Biozentrum University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Karrer\u2010Cardel","sequence":"additional","affiliation":[{"name":"Biozentrum University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Sagot","sequence":"additional","affiliation":[{"name":"Sonnet Biotherapeutics CH SA  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0603-1097","authenticated-orcid":false,"given":"Christoph","family":"Handschin","sequence":"additional","affiliation":[{"name":"Biozentrum University of Basel  Basel 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