Hyperphosphatemia Contributes to Skeletal Muscle Atrophy in the Absence and Presence of Chronic Kidney Disease

无论是否患有慢性肾病,高磷血症都会导致骨骼肌萎缩

基本信息

  • 批准号:
    10624782
  • 负责人:
  • 金额:
    $ 4.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-05-01 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Chronic kidney disease (CKD) is a health epidemic that increases risk of death due to various comorbidities. Alterations in mineral metabolism are a hallmark of advanced CKD, where elevations in serum phosphate levels (hyperphosphatemia) have been suspected to directly contribute to tissue damage and mortality. Hyperphosphatemia is clinically tackled in CKD patients by administration of phosphate binders and introduction of low phosphate diets. While the contributions of hyperphosphatemia to vascular calcification have been established and the underlying signaling mechanism in vascular smooth muscle cells has been studied, the potential direct effects of elevated phosphate on other tissues and cell types are not understood. In our study, we focus on skeletal muscle wasting and atrophy which affects many patients with CKD. In our preliminary studies, we have characterized the skeletal muscle phenotype in two mouse models of CKD, one genetic and one diet-induced, and our molecular, histological and functional analyses indicate reduced muscle strength and mass as well as reduced size of individual myofibers and activation of atrophy gene programs. Since these mice develop hyperphosphatemia, and our preliminary in vitro studies indicate that phosphate elevations can induce atrophy in differentiated skeletal muscle cells (myotubes), we hypothesize that in CKD, elevated serum phosphate levels can directly affect skeletal muscle tissue and contribute to skeletal muscle wasting. Since phosphate uptake via specific phosphate transporters is essential for all cells and tissues for house-keeping functions and survival, we cannot use loss-of-function approaches to study the direct effects of phosphate on skeletal muscle in mice. Instead, we will determine whether administration of a low phosphate diet, when initiated early on, protects CKD mice from developing skeletal muscle atrophy. Our phenotypic analyses will include structural and functional studies by MRI and histology, and also focus on fibrosis, inflammation and increased fat content which are observed in skeletal muscle tissue of CKD patients. Our in vivo study is accompanied by cell culture experiments which analyze direct effects of phosphate on myotubes. We will determine the involvement of phosphate transporters and the signaling mechanisms that mediate phosphate-induced atrophy in cultured myotubes. Our preliminary studies also indicate that healthy mice receiving a high phosphate diet for three months develop signs of skeletal muscle atrophy. While the injury seems to be milder than in CKD mice, this finding indicates that hyperphosphatemia by itself, in the absence of kidney injury, can damage skeletal muscle. We will determine if prolonged administration of a high phosphate diet further increases skeletal muscle damage, and whether after three months of high phosphate diet the transition to a diet with normal phosphate content reverses skeletal muscle injury. If successful, our study would indicate that lowering phosphate in CKD has protective effects on skeletal muscle tissue, and that diets rich in phosphate salts, such as all processed foods, can cause skeletal muscle injury in healthy individuals.
项目摘要 慢性肾脏病(CKD)是一种健康流行病,由于各种合并症而增加死亡风险。 矿物质代谢的改变是晚期CKD的一个标志, 高磷酸盐水平(高磷酸盐血症)被怀疑直接导致组织损伤和死亡。 高磷酸盐血症在临床上通过给予磷酸盐结合剂和 采用低磷饮食。虽然高磷血症对血管钙化的贡献 已经建立,并且血管平滑肌细胞中的潜在信号传导机制已经建立, 尽管已经进行了研究,但尚不清楚磷酸盐升高对其他组织和细胞类型的潜在直接影响。在 在我们的研究中,我们关注影响许多CKD患者的骨骼肌萎缩和萎缩。在我们 初步研究,我们已经在两种CKD小鼠模型中表征了骨骼肌表型, 遗传和饮食诱导,我们的分子,组织学和功能分析表明,减少肌肉 强度和质量以及个体肌纤维的尺寸减小和萎缩基因程序的激活。 由于这些小鼠发展为高磷酸盐血症,我们的初步体外研究表明,磷酸盐 升高可诱导分化的骨骼肌细胞(肌管)萎缩,我们假设在CKD中, 血清磷酸盐水平升高可直接影响骨骼肌组织, 浪费由于通过特异性磷酸盐转运蛋白的磷酸盐摄取对于所有细胞和组织是必需的, 管家功能和生存,我们不能使用功能丧失的方法来研究的直接影响, 磷酸盐对小鼠骨骼肌的影响。相反,我们将决定是否给予低磷酸盐 早期开始的饮食可保护CKD小鼠免于发生骨骼肌萎缩。我们的表型 分析将包括通过MRI和组织学进行的结构和功能研究,并关注纤维化, 在CKD患者的骨骼肌组织中观察到的炎症和增加的脂肪含量。我们在 体内研究伴随着分析磷酸盐对肌管的直接作用的细胞培养实验。 我们将确定磷酸盐转运蛋白的参与和介导的信号机制, 磷酸盐诱导的肌管萎缩。我们的初步研究还表明, 接受高磷酸盐饮食三个月会出现骨骼肌萎缩的迹象。虽然受伤 似乎比慢性肾病小鼠的症状要轻,这一发现表明,在没有磷酸盐的情况下,高磷酸盐血症本身就存在。 肾损伤,可损伤骨骼肌。我们将确定是否长期使用高磷酸盐 饮食进一步增加骨骼肌损伤,以及是否经过三个月的高磷酸盐饮食, 过渡到磷酸盐含量正常的饮食可逆转骨骼肌损伤。如果成功,我们的研究 这表明降低CKD中的磷酸盐对骨骼肌组织具有保护作用, 富含磷酸盐的食物,如所有加工食品,会导致健康个体的骨骼肌损伤。

项目成果

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Kylie Heitman其他文献

Kylie Heitman的其他文献

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{{ truncateString('Kylie Heitman', 18)}}的其他基金

Hyperphosphatemia Contributes to Skeletal Muscle Atrophy in the Absence and Presence of Chronic Kidney Disease
无论是否患有慢性肾病,高磷血症都会导致骨骼肌萎缩
  • 批准号:
    10389333
  • 财政年份:
    2022
  • 资助金额:
    $ 4.77万
  • 项目类别:

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