Muscle fibrosis and maladaptation occur progressively in CKD and are rescued by dialysis.
Muscle fibrosis and maladaptation occur progressively in CKD and are rescued by dialysis.
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DOI：
10.1172/jci.insight.150112
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发表时间：
2021-12-22
期刊：
影响因子：
8
通讯作者：
Abramowitz MK
中科院分区：
文献类型：
--
作者：
Brightwell CR;Kulkarni AS;Paredes W;Zhang K;Perkins JB;Gatlin KJ;Custodio M;Farooq H;Zaidi B;Pai R;Buttar RS;Tang Y;Melamed ML;Hostetter TH;Pessin JE;Hawkins M;Fry CS;Abramowitz MK
骨骼肌适应不良伴随慢性肾病（CKD）并对身体功能产生负面影响。历史上 CKD 的重点一直放在肌纤维内在缺陷上，例如蛋白质代谢改变和萎缩。然而，纤维内在功能障碍的靶向治疗取得的改善有限，而纤维外在环境内的改变几乎没有被检查过。我们通过对 CKD 患者和年龄匹配对照的活检进行深层细胞表型分析，研究了骨骼肌间质环境的改变，并进行了转录组分析，以确定 CKD 相关肌肉损伤的分子基础。我们检查了肾衰竭透析治疗开始后肌肉适应不良的变化。慢性肾病患者表现出进行性纤维化肌肉表型，这与再生能力受损和血管密度降低有关。这些缺陷的严重程度与肾功能障碍的程度密切相关。与这些严重缺陷相一致，CKD 与肌肉转录组的广泛改变有关，包括 ECM 组织改变、血管生成下调以及干细胞自我更新相关通路表达改变。值得注意的是，尽管这种纤维化转变看似先进，但透析治疗挽救了这些缺陷，恢复了更健康的肌肉表型。此外，考虑到肌肉萎缩后，透析开始后力量和耐力得到改善。这些数据确定了 CKD 中的透析反应性肌肉纤维化表型，并表明早期透析窗口提供了改善肌肉再生能力的独特机会，在此期间有针对性的干预措施可能会产生最大的影响。 NCT01452412 NIH、NIH 临床和转化科学奖 (CTSA) 和爱因斯坦西奈山糖尿病研究中心
Skeletal muscle maladaptation accompanies chronic kidney disease (CKD) and negatively affects physical function. Emphasis in CKD has historically been placed on muscle fiber–intrinsic deficits, such as altered protein metabolism and atrophy. However, targeted treatment of fiber-intrinsic dysfunction has produced limited improvement, whereas alterations within the fiber-extrinsic environment have scarcely been examined. We investigated alterations to the skeletal muscle interstitial environment with deep cellular phenotyping of biopsies from patients with CKD and age-matched controls and performed transcriptome profiling to define the molecular underpinnings of CKD-associated muscle impairments. We examined changes in muscle maladaptation following initiation of dialysis therapy for kidney failure. Patients with CKD exhibited a progressive fibrotic muscle phenotype, which was associated with impaired regenerative capacity and lower vascular density. The severity of these deficits was strongly associated with the degree of kidney dysfunction. Consistent with these profound deficits, CKD was associated with broad alterations to the muscle transcriptome, including altered ECM organization, downregulated angiogenesis, and altered expression of pathways related to stem cell self-renewal. Remarkably, despite the seemingly advanced nature of this fibrotic transformation, dialysis treatment rescued these deficits, restoring a healthier muscle phenotype. Furthermore, after accounting for muscle atrophy, strength and endurance improved after dialysis initiation. These data identify a dialysis-responsive muscle fibrotic phenotype in CKD and suggest the early dialysis window presents a unique opportunity of improved muscle regenerative capacity during which targeted interventions may achieve maximal impact. NCT01452412 NIH, NIH Clinical and Translational Science Awards (CTSA), and Einstein-Mount Sinai Diabetes Research Center
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影响因子：
5.5
作者：
Cheng, Ming;Nguyen, Mai-Huong;Koh, Timothy J.
通讯作者：
Koh, Timothy J.
影响因子：
158.5
作者：
Cooper, Bruce A.;Branley, Pauline;Pollock, Carol A.
通讯作者：
Pollock, Carol A.
影响因子：
64.8
作者：
Conboy, IM;Conboy, MJ;Rando, TA
通讯作者：
Rando, TA
在慢性肾脏疾病中，骨骼肌再生和氧化应激发生了改变。
影响因子：
3.7
作者：
Avin KG;Chen NX;Organ JM;Zarse C;O'Neill K;Conway RG;Konrad RJ;Bacallao RL;Allen MR;Moe SM
通讯作者：
Moe SM
影响因子：
13.2
作者：
Daugirdas, John T.;Depner, Thomas A.;Weiner, Daniel E.
通讯作者：
Weiner, Daniel E.