PMID- 35073463 OWN - NLM STAT- MEDLINE DCOM- 20220309 LR - 20240405 IS - 2001-1326 (Electronic) IS - 2001-1326 (Linking) VI - 12 IP - 1 DP - 2022 Jan TI - Interventional- and amputation-stage muscle proteomes in the chronically threatened ischemic limb. PG - e658 LID - 10.1002/ctm2.658 [doi] LID - e658 AB - BACKGROUND: Despite improved surgical approaches for chronic limb-threatening ischemia (CLTI), amputation rates remain high and contributing tissue-level factors remain unknown. 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. METHODS AND RESULTS: Gastrocnemius muscle was collected from non-ischemic controls (n = 19) and either pre-interventional surgery (n = 10) or at amputation outcome (n = 29) CLTI patients. All samples were subjected to isobaric tandem-mass-tag-assisted proteomics. The mitochondrion was the primary classification of downregulated proteins (> 70%) in CLTI limb muscles and paralleled robust functional mitochondrial impairment. Upregulated proteins (> 38%) were largely from the extracellular matrix. Across the two independent sites, 39 proteins were downregulated and 12 upregulated uniformly. Pre-interventional CLTI muscles revealed a robust upregulation of mitochondrial proteins but modest functional impairments in fatty acid oxidation as compared with controls. Comparison of pre-intervention and amputation CLTI limb muscles revealed mitochondrial proteome and functional deficits similar to that between amputation and non-ischemic controls. Interestingly, these observed changes occurred despite 62% of the amputation CLTI patients having undergone a prior surgical intervention. CONCLUSIONS: The CLTI proteome supports failing mitochondria as a phenotype that is unique to amputation outcomes. The signature of pre-intervention 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. CI - (c) 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. FAU - Ryan, Terence E AU - Ryan TE AUID- ORCID: 0000-0003-0780-029X AD - Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA. AD - Center for Exercise Science, University of Florida, Gainesville, Florida, USA. AD - Myology Institute, University of Florida, Gainesville, Florida, USA. FAU - Kim, Kyoungrae AU - Kim K AD - Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA. FAU - Scali, Salvatore T AU - Scali ST AD - Division of Vascular Surgery and Endovascular Therapy, University of Florida, Gainesville, Florida, USA. AD - Malcom Randall Veteran Affairs Medical Center, Gainesville, Florida, USA. FAU - Berceli, Scott A AU - Berceli SA AD - Division of Vascular Surgery and Endovascular Therapy, University of Florida, Gainesville, Florida, USA. AD - Malcom Randall Veteran Affairs Medical Center, Gainesville, Florida, USA. FAU - Thome, Trace AU - Thome T AD - Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA. FAU - Salyers, Zachary R AU - Salyers ZR AD - Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA. FAU - O'Malley, Kerri A AU - O'Malley KA AD - Division of Vascular Surgery and Endovascular Therapy, University of Florida, Gainesville, Florida, USA. AD - Malcom Randall Veteran Affairs Medical Center, Gainesville, Florida, USA. FAU - Green, Thomas D AU - Green TD AD - Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA. AD - East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA. FAU - Karnekar, Reema AU - Karnekar R AD - Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA. AD - East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA. FAU - Fisher-Wellman, Kelsey H AU - Fisher-Wellman KH AD - Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA. AD - East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA. FAU - Yamaguchi, Dean J AU - Yamaguchi DJ AD - Department of Cardiovascular Science, East Carolina University, Greenville, North Carolina, USA. AD - Division of Surgery, East Carolina University, Greenville, North Carolina, USA. FAU - McClung, Joseph M AU - McClung JM AD - Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA. AD - East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA. AD - Department of Cardiovascular Science, East Carolina University, Greenville, North Carolina, USA. LA - eng GR - R01 HL150003/HL/NHLBI NIH HHS/United States GR - P30 AG028740/AG/NIA NIH HHS/United States GR - R01 HL149704/HL/NHLBI NIH HHS/United States GR - 18CDA34110044/American Heart Association/ GR - W81XWH-19-1-0213/U.S. Department of Defense/ GR - R01 HL148597/HL/NHLBI NIH HHS/United States GR - R01 HL157659/HL/NHLBI NIH HHS/United States GR - R01 DK119274/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Transl Med JT - Clinical and translational medicine JID - 101597971 RN - 0 (Proteome) SB - IM MH - Aged MH - Aged, 80 and over MH - Chronic Limb-Threatening Ischemia/complications/pathology/*physiopathology MH - Cross-Sectional Studies MH - Extremities/blood supply/innervation/physiopathology MH - Female MH - Florida MH - Humans MH - Male MH - Muscle, Skeletal/drug effects/physiopathology MH - North Carolina MH - Proteome/metabolism/*pharmacology MH - Risk Factors PMC - PMC8785983 OTO - NOTNLM OT - metabolism OT - peripheral artery disease OT - surgery OT - vascular disease EDAT- 2022/01/25 06:00 MHDA- 2022/03/11 06:00 PMCR- 2022/01/24 CRDT- 2022/01/24 17:15 PHST- 2021/11/05 00:00 [revised] PHST- 2021/09/10 00:00 [received] PHST- 2021/11/11 00:00 [accepted] PHST- 2022/01/24 17:15 [entrez] PHST- 2022/01/25 06:00 [pubmed] PHST- 2022/03/11 06:00 [medline] PHST- 2022/01/24 00:00 [pmc-release] AID - CTM2658 [pii] AID - 10.1002/ctm2.658 [doi] PST - ppublish SO - Clin Transl Med. 2022 Jan;12(1):e658. doi: 10.1002/ctm2.658.