Interventional- and amputation-stage muscle proteomes in the chronically threatened ischemic limb

ABSTRACT: Background: Despite improved surgical approaches for chronic limb threatening ischemia (CLTI), amputation rates remain high and contributing tissue-level factors remain unknown. Objective: 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: Gastrocnemius muscle was collected from non-ischemic control (n=26) 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 quantitative proteomics. Results: 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 20 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 healthy controls. Interestingly, these observed changes occurred despite 50% of the amputation CLTI patients having undergone a prior surgical intervention. Conclusions: The CLTI proteome supports failing mitochondria as a mechanism contributing 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, our findings support the investigation of mitochondrial functional therapeutics as both adjuvant and independent therapies for CLTI.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Kelsey Fisher-Wellman 

PROVIDER: PXD025810 | JPOST Repository | Thu Apr 21 00:00:00 BST 2022

REPOSITORIES: jPOST