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Given the negative energy balance during sodium\u2013glucose cotransporter\u20102 (SGLT2) inhibition, whether SGLT2 inhibitors affect skeletal muscle mass and function is a matter of concern. However, how SGLT2 inhibition affects the skeletal muscle function in patients with diabetes remains insufficiently explored. We aimed to explore the effects of canagliflozin (CANA), an SGLT2 inhibitor, on skeletal muscles in genetically diabetic <jats:italic>db\/db<\/jats:italic> mice focusing on the differential responses of oxidative and glycolytic muscles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>Db<\/jats:italic>\/<jats:italic>db<\/jats:italic> mice were treated with CANA for 4\u00a0weeks. We measured running distance and handgrip strength to assess skeletal muscle function during CANA treatment. At the end of the experiment, we performed a targeted metabolome analysis of the skeletal muscles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CANA treatment improved the reduced endurance capacity, as revealed by running distance in <jats:italic>db<\/jats:italic>\/<jats:italic>db<\/jats:italic> mice (414.9\u00a0\u00b1\u00a052.8 vs. 88.7\u00a0\u00b1\u00a022.7\u00a0m, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Targeted metabolome analysis revealed that 5\u2010aminoimidazole\u20104\u2010carboxamide\u20101\u2010\u03b2\u2010D\u2010ribofuranosyl 5\u2032\u2010monophosphate (AICARP), a naturally occurring AMP\u2010activated protein kinase (AMPK) activator, increased in the oxidative soleus muscle (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), but not in the glycolytic extensor digitorum longus muscle (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.4376), with increased levels of AMPK phosphorylation (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study highlights the potential role of the AICARP\/AMPK pathway in oxidative rather than glycolytic skeletal muscles during SGLT2 inhibition, providing novel insights into the mechanism by which SGLT2 inhibitors improve endurance capacity in patients with type 2 diabetes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13350","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T05:02:37Z","timestamp":1699506157000},"page":"2866-2881","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Improved endurance capacity of diabetic mice during SGLT2 inhibition: Role of AICARP, an AMPK activator in the soleus"],"prefix":"10.1002","volume":"14","author":[{"given":"Shintaro","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1487-5153","authenticated-orcid":false,"given":"Yasutaka","family":"Miyachi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences 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