Interventional- and amputation-stage muscle proteomes in the chronically threatened ischemic limb.
Interventional- and amputation-stage muscle proteomes in the chronically threatened ischemic limb.
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DOI：
10.1002/ctm2.658
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发表时间：
2022-01
影响因子：
10.6
通讯作者：
McClung JM
中科院分区：
文献类型：
--
作者：
Ryan TE;Kim K;Scali ST;Berceli SA;Thome T;Salyers ZR;O'Malley KA;Green TD;Karnekar R;Fisher-Wellman KH;Yamaguchi DJ;McClung JM
尽管慢性威胁肢体缺血（CLTI）的手术方法有所改进，但截肢率仍然很高，组织水平的影响因素仍然未知。本研究的目的有两个：（1）确定健康成人和CLTI肢体肌肉蛋白质组之间的差异，以及（2）确定手术干预前或截肢时CLTI患者肢体肌肉蛋白质组的差异。从非缺血对照（n = 19）和介入手术前（n = 10）或截肢结局（n = 29）CLTI患者中采集腓肠肌。所有样本均进行了同量异位串联质量标签辅助蛋白质组学。在CLTI肢体肌肉中下调的蛋白质（> 70%）的主要分类是线粒体功能障碍。上调的蛋白质（> 38%）主要来自细胞外基质。在两个独立的网站，39个蛋白质下调和12上调一致。与对照组相比，干预前CLTI肌肉显示线粒体蛋白质的稳健上调，但脂肪酸氧化功能受损适度。干预前和截肢CLTI肢体肌肉的比较显示，线粒体蛋白质组和功能缺陷与截肢和非缺血对照之间相似。有趣的是，尽管62%的截肢CLTI患者接受了既往手术干预，但仍发生了这些观察到的变化。CLTI蛋白质组支持线粒体衰竭是截肢结果所特有的表型。干预前CLTI肌肉的特征显示稳定的线粒体蛋白丰度不足以均匀地预防功能障碍。总之，这些发现支持了未来纵向调查的需要，旨在确定线粒体功能衰竭是否与CLTI的截肢结果有因果关系。CLTI肌肉标本的蛋白质组学分析确定了一种独特的肢体肌肉蛋白质组特征，其特征在于截肢阶段标本中的严重脊髓病变，发现其与非PAD对照和CLTI术前干预肢体肌肉不同。与蛋白质组特征一致，截肢期CLTI标本中线粒体功能严重受损。与非PAD对照相比，介入期CLTI标本显示线粒体蛋白质组上调;然而，这并未改善线粒体氧化磷酸化。
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. 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. 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. Proteomic analyses of CLTI muscle specimens identify a distinct limb muscle proteome signature characterized by a severe mitochondriopathy in amputation‐stage specimens, which was discovered to differ from non‐PAD controls and CLTI pre‐surgical intervention limb muscles. Coincident with the proteome signature, mitochondrial function was severely impaired in amputation‐stage CLTI specimens. Compared to non‐PAD controls, interventional‐stage CLTI specimens displayed an upregulation of the mitochondrial proteome; however, this did not afford any improvement in mitochondrial oxidative phosphorylation.
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影响因子：
24
作者：
McDermott, Mary M.;Liu, Kiang;Criqui, Michael H.
通讯作者：
Criqui, Michael H.
影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
影响因子：
24
作者：
Jain A;Liu K;Ferrucci L;Criqui MH;Tian L;Guralnik JM;Tao H;McDermott MM
通讯作者：
McDermott MM
影响因子：
4.3
作者：
Jain, Atul;Liu, Kiang;McDermott, Mary M.
通讯作者：
McDermott, Mary M.
影响因子：
14.9
作者：
Deutsch EW;Csordas A;Sun Z;Jarnuczak A;Perez-Riverol Y;Ternent T;Campbell DS;Bernal-Llinares M;Okuda S;Kawano S;Moritz RL;Carver JJ;Wang M;Ishihama Y;Bandeira N;Hermjakob H;Vizcaíno JA
通讯作者：
Vizcaíno JA