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We asked whether inflexibility in metabolism is critical for the development of myopathy in ischemic limb muscles. Using Polg mtDNA mutator (D257A) mice, we reveal remarkable protection from hind limb ischemia (HLI) due to a unique and beneficial adaptive enhancement of glycolytic metabolism and elevated ischemic muscle PFKFB3. Similar to the relationship between mitochondria from CLI and claudicating patient muscles, BALB\/c muscle mitochondria are uniquely dysfunctional after HLI onset as compared with the C57BL\/6 (BL6) parental strain. AAV-mediated overexpression of PFKFB3 in BALB\/c limb muscles improved muscle contractile function and limb blood flow following HLI. Enrichment analysis of RNA sequencing data on muscle from CLI patients revealed a unique deficit in the glucose metabolism Reactome. Muscles from these patients express lower PFKFB3 protein, and their muscle progenitor cells possess decreased glycolytic flux capacity in vitro. Here, we show supplementary glycolytic flux as sufficient to protect against ischemic myopathy in instances where reduced blood flow\u2013related mitochondrial function is compromised preclinically. Additionally, our data reveal reduced glycolytic flux as a common characteristic of the failing CLI patient limb skeletal muscle.<\/jats:p>","DOI":"10.1172\/jci.insight.139628","type":"journal-article","created":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T12:15:46Z","timestamp":1598357746000},"source":"Crossref","is-referenced-by-count":40,"title":["PFKFB3-mediated glycolysis rescues myopathic outcomes in the ischemic limb"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0780-029X","authenticated-orcid":true,"given":"Terence E.","family":"Ryan","sequence":"first","affiliation":[{"name":"East Carolina Diabetes and Obesity Institute,"},{"name":"Department of Physiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron A.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"East Carolina Diabetes and Obesity Institute,"},{"name":"Department of Physiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Tarpey","sequence":"additional","affiliation":[{"name":"East Carolina Diabetes and Obesity Institute,"},{"name":"Department of Physiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9661-0203","authenticated-orcid":true,"given":"Adam J.","family":"Amorese","sequence":"additional","affiliation":[{"name":"East Carolina Diabetes and Obesity Institute,"},{"name":"Department of Physiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean J.","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Science, and"},{"name":"Division of Surgery, East Carolina University, Brody School of Medicine, Greenville, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma J.","family":"Goldberg","sequence":"additional","affiliation":[{"name":"East Carolina Diabetes and Obesity Institute,"},{"name":"Department of Physiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa M.R.","family":"I\u00f1igo","sequence":"additional","affiliation":[{"name":"East Carolina Diabetes and Obesity Institute,"},{"name":"Department of Physiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reema","family":"Karnekar","sequence":"additional","affiliation":[{"name":"East Carolina Diabetes and Obesity Institute,"},{"name":"Department of Physiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"O\u2019Rourke","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota, Saint Paul, Minnesota, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Ervasti","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota, Saint Paul, Minnesota, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Brophy","sequence":"additional","affiliation":[{"name":"East Carolina Diabetes and Obesity Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D.","family":"Green","sequence":"additional","affiliation":[{"name":"East Carolina Diabetes and Obesity Institute,"},{"name":"Department of Physiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2256-6051","authenticated-orcid":true,"given":"P. 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