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The purpose of this study was twofold: (1) to identify differences between the healthy adult and CLTI limb muscle proteome, and (2) to identify differences in the limb muscle proteome of CLTI patients prior to surgical intervention or at the time of amputation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Gastrocnemius muscle was collected from non\u2010ischemic controls (n\u00a0=\u00a019) and either pre\u2010interventional surgery (n\u00a0=\u00a010) or at amputation outcome (n\u00a0=\u00a029) CLTI patients. All samples were subjected to isobaric tandem\u2010mass\u2010tag\u2010assisted proteomics. The mitochondrion was the primary classification of downregulated proteins (&gt;\u00a070%) in CLTI limb muscles and paralleled robust functional mitochondrial impairment. Upregulated proteins (&gt;\u00a038%) were largely from the extracellular matrix. Across the two independent sites, 39 proteins were downregulated and 12 upregulated uniformly. Pre\u2010interventional CLTI muscles revealed a robust upregulation of mitochondrial proteins but modest functional impairments in fatty acid oxidation as compared with controls. Comparison of pre\u2010intervention and amputation CLTI limb muscles revealed mitochondrial proteome and functional deficits similar to that between amputation and non\u2010ischemic controls. Interestingly, these observed changes occurred despite 62% of the amputation CLTI patients having undergone a prior surgical intervention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The CLTI proteome supports failing mitochondria as a phenotype that is unique to amputation outcomes. The signature of pre\u2010intervention CLTI muscle reveals stable mitochondrial protein abundance that is insufficient to uniformly prevent functional impairments. Taken together, these findings support the need for future longitudinal investigations aimed to determine whether mitochondrial failure is causally involved in amputation outcomes from CLTI.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.658","type":"journal-article","created":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T18:06:23Z","timestamp":1643047583000},"source":"Crossref","is-referenced-by-count":18,"title":["Interventional\u2010 and amputation\u2010stage muscle proteomes in the chronically threatened ischemic limb"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0780-029X","authenticated-orcid":false,"given":"Terence E.","family":"Ryan","sequence":"first","affiliation":[{"name":"Department of Applied Physiology and Kinesiology University of Florida  Gainesville Florida USA"},{"name":"Center for Exercise Science University of Florida  Gainesville Florida USA"},{"name":"Myology Institute University of Florida  Gainesville Florida 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