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：
10389333
负责人：
Kylie Heitman
金额：
$ 4.68万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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

来源：
https://reporter.nih.gov/project-details/10389333
关键词：
Adenine Affect Age Area Atrophic Biological Markers Blood Cardiovascular Diseases Cell Culture Techniques Cells Cessation of life Chronic Kidney Failure Clinical Collagen Data Development Diet Epidemic FGFR1 gene FGFR4 gene Fatty acid glycerol esters Fibroblast Growth Factor Receptors Fibrosis Food Genes Genetic Hand Strength Health Heart Hypertrophy Heart Injuries Hindlimb Histologic Histology Hormones Housekeeping In Vitro Individual Inflammation Injury Injury to Kidney Inorganic Phosphate Transporter Intake Kidney Knockout Mice Link Lipids MAPK3 gene Magnetic Resonance Imaging Mediating Metabolism Minerals Mitogen-Activated Protein Kinases Molecular Molecular Analysis Monitor Mus Muscle Muscle Fibers Muscular Atrophy Myoblasts Outcome PTH gene Pathologic Pathology Patients Phenotype Physiological Process Protein Isoforms Renal function Reporting Research Proposals Rodent Salts Serum Severity of illness Signal Pathway Signal Transduction Skeletal Muscle Skeletal muscle injury Smooth Muscle Myocytes Study of magnetics Time Tissues Tubular formation Up-Regulation Vascular Smooth Muscle Vascular calcification Vitamin D Western Blotting Wild Type Mouse bone cell type clinical practice comorbidity experimental study fibroblast growth factor 23 improved in vivo inhibitor inorganic phosphate knock-down loss of function mortality mortality risk mouse model muscle form novel phospholipase C gamma premature prevent programs protective effect receptor reduced muscle strength skeletal muscle differentiation skeletal muscle wasting systemic inflammatory response tissue injury uptake

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.

项目概要慢性肾病 (CKD) 是一种健康流行病，会因各种合并症而增加死亡风险。矿物质代谢的改变是晚期 CKD 的标志，其中血清磷酸盐升高水平（高磷血症）被怀疑直接导致组织损伤和死亡。 CKD 患者的高磷血症临床上通过给予磷酸盐结合剂和引入低磷酸盐饮食。而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的潜在信号机制已经被阐明研究表明，磷酸盐升高对其他组织和细胞类型的潜在直接影响尚不清楚。在我们的研究重点关注影响许多 CKD 患者的骨骼肌消耗和萎缩。在我们的初步研究中，我们对两种 CKD 小鼠模型的骨骼肌表型进行了表征，其中一种遗传和饮食引起的，我们的分子、组织学和功能分析表明肌肉减少强度和质量以及单个肌纤维尺寸的减小和萎缩基因程序的激活。由于这些小鼠出现高磷酸盐血症，我们的初步体外研究表明磷酸盐升高会引起分化的骨骼肌细胞（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并有助于骨骼肌浪费。由于通过特定磷酸盐转运蛋白的磷酸盐摄取对于所有细胞和组织的生命活动至关重要。家务功能和生存，我们不能使用功能丧失的方法来研究磷酸盐对小鼠骨骼肌的影响。相反，我们将确定是否施用低磷酸盐早期开始饮食可以保护 CKD 小鼠免于出现骨骼肌萎缩。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，并且还关注纤维化，在 CKD 患者的骨骼肌组织中观察到炎症和脂肪含量增加。我们在体内研究伴随着细胞培养实验，分析磷酸盐对肌管的直接影响。我们将确定磷酸盐转运蛋白的参与以及介导的信号机制培养的肌管中磷酸盐诱导的萎缩。我们的初步研究还表明，健康的小鼠接受高磷酸盐饮食三个月会出现骨骼肌萎缩的迹象。受伤的同时似乎比 CKD 小鼠更温和，这一发现表明高磷血症本身，在没有肾损伤，会损伤骨骼肌。我们将确定是否长期服用高磷酸盐饮食进一步增加骨骼肌损伤，三个月的高磷酸盐饮食是否会导致骨骼肌损伤？过渡到磷酸盐含量正常的饮食可以逆转骨骼肌损伤。如果成功的话，我们的研究表明降低 CKD 中的磷酸盐对骨骼肌组织具有保护作用，并且饮食富含磷酸盐的食物，例如所有加工食品，可能会导致健康个体骨骼肌损伤。