权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Isoform-specific roles of the Na,K-ATPase in skeletal muscle

Na,K-ATP 酶在骨骼肌中的异构体特异性作用

基本信息

批准号：
9335266
负责人：
JUDITH A HEINY
金额：
$ 47.61万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335266
关键词：
ATP1A2 gene Action Potentials Acute Adrenergic Agonists Adrenergic Receptor Adult Agonist Animal Model Animals Biochemical Biological Assay Cachexia Chronic Obstructive Airway Disease Collaborations Contracts Coronary artery Data Disease Enzymes Event Exercise Fatigue Gene Targeting Genes Genetic Genetic Models Health Heart failure Home environment Housekeeping Image Impairment In Vitro International Ligation Measurement Measures Membrane Potentials Molecular Molecular Target Mus Muscle Muscle Contraction Muscle Fatigue Muscle Weakness Muscle function Muscular Dystrophies Na(+)-K(+)-Exchanging ATPase Outcome Study Performance Phosphorylation Physiological Play Positioning Attribute Property Protein Isoforms Public Health Receptor Activation Regulation Research Resistance Resources Rest Role Skeletal Muscle Testing Therapeutic Intervention Tissues Universities Up-Regulation beta-2 Adrenergic Receptors enzyme activity exercise intolerance extracellular genetic manipulation in vivo membrane excitation molecular targeted therapies mouse model novel phospholemman public health relevance resistance mechanism sarcopenia therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Skeletal muscle weakness and fatigue is a common, debilitating condition in heart failure, sarcopenia, cachexia, muscular dystrophies, COPD, and other disorders. Na,K-ATPase activity is dramatically stimulated during muscle contraction and is absolutely required to maintain force and exercise performance. However, few studies have examined the role the Na,K-ATPase isoforms in muscle weakness and fatigue. Adult skeletal muscles express mainly the α2 isoform of the Na,K-ATPase, in contrast to most other tissues which express mainly the α1 isoform. The role of the α2 isoform in skeletal muscle and the mechanisms by which its activity is stimulated are not known. The central hypotheses of this research is that the Na,K-ATPase α2 isoform provides a reserve capacity which is largely inactive at rest but is rapidly stimulated during contraction, to meet the increased demand for Na/K transport; and that its regulation is achieved in part by phosphorylation of the muscle-specific FXYD1 subunit of the Na,K-ATPase. This hypothesis will be tested using a novel gene targeted mouse which specifically lacks the Na,K-ATPase α2 in adult skeletal muscles (skα2-/-) and shows marked exercise intolerance and skeletal muscle weakness. The Specific Aims are to: 1) Determine the acute role of the Na,K-ATPase α2 enzyme in maintaining force and exercise performance; 2) Determine the role of the Na,K-ATPase α2 enzyme in membrane excitation in the transverse tubules and resistance to fatigue; and 3) a, Define the role of FXYD1 phosphorylation in the acute stimulation of Na,K-ATPase α2 activity by α2- adrenergic receptor activation during contraction; b, Determine the contribution of altered Na,K-ATPase content or function to muscle fatigue and exercise intolerance in heart failure. These Aims will be approached using an integrated strategy which combines genetic manipulations in the mouse with functional measurements from the animal to the cellular and subcellular level. Collectively, this project will advance our understanding of the physiological roles of the Na,K-ATPase α2 isoform and the mechanisms by which it is regulated in skeletal muscle, and identify new molecular targets for therapeutic interventions in muscle weakness and fatigue.

描述（由申请人提供）：骨骼肌无力和疲劳是心力衰竭、肌肉减少症、恶病质、肌肉营养不良症、慢性阻塞性肺病和其他疾病中常见的衰弱状态。Na， k - atp酶活性在肌肉收缩过程中被显著刺激，这是维持力量和运动表现所绝对需要的。然而，很少有研究检查Na， k - atp酶同工型在肌肉无力和疲劳中的作用。成人骨骼肌主要表达Na， k - atp酶的α2亚型，而其他组织主要表达α1亚型。α2亚型在骨骼肌中的作用及其激活机制尚不清楚。本研究的中心假设是，Na，K- atp酶α2亚型提供了一种储备能力，这种储备能力在休息时基本不活跃，但在收缩时迅速激活，以满足Na/K运输的增加需求；它的调节部分是通过Na - k - atp酶的肌肉特异性FXYD1亚基的磷酸化来实现的。这一假设将通过一种新的基因来验证，该基因靶向小鼠在成年骨骼肌中特异性缺乏Na， k - atp酶α2 (skα2-/-)，并表现出明显的运动不耐受和骨骼肌无力。具体目的是：1)确定Na， k - atp酶α2酶在维持力量和运动表现中的急性作用；2)确定Na、k - atp酶α2酶在横小管膜兴奋和抗疲劳中的作用；3) a，明确FXYD1磷酸化在收缩时α2-肾上腺素能受体激活对Na， k - atp酶α2活性的急性刺激中的作用；b、确定Na、k - atp酶含量或功能改变对心力衰竭患者肌肉疲劳和运动不耐受的影响。这些目标将采用一种综合策略来实现，该策略将小鼠的遗传操作与从动物到细胞和亚细胞水平的功能测量相结合。总的来说，该项目将促进我们对Na， k - atp酶α2亚型的生理作用及其在骨骼肌中的调节机制的理解，并为肌肉无力和疲劳的治疗干预确定新的分子靶点。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Isoform-specific Na,K-ATPase alterations precede disuse-induced atrophy of rat soleus muscle.

异构体特异性 Na,K-ATP 酶改变先于废用引起的大鼠比目鱼肌萎缩。

DOI：
10.1155/2015/720172
发表时间：
2015
期刊：
BioMed research international
影响因子：
0
作者：
Kravtsova,ViolettaV;Matchkov,VladimirV;Bouzinova,ElenaV;Vasiliev,AlexanderN;Razgovorova,IrinaA;Heiny,JudithA;Krivoi,IgorI
通讯作者：
Krivoi,IgorI

Canonical Bcl-2 Motifs of the Na+/K+ Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

DOI：
10.1159/000343366
发表时间：
2013-02
期刊：
Cellular Physiology and Biochemistry
影响因子：
0
作者：
P. Lauf;J. Heiny;J. Meller;Michael Lepera;L. Koikov;G. Alter;T. Brown;N. Adragna
通讯作者：
P. Lauf;J. Heiny;J. Meller;Michael Lepera;L. Koikov;G. Alter;T. Brown;N. Adragna

Transient Receptor Potential Vanilloid 2 Regulates Myocardial Response to Exercise.

瞬时受体电位香草酸 2 调节心肌对运动的反应。

DOI：
10.1371/journal.pone.0136901
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Naticchioni,Mindi;Karani,Rajiv;Smith,MargaretA;Onusko,Evan;Robbins,Nathan;Jiang,Min;Radzyukevich,Tatiana;Fulford,Logan;Gao,Xu;Apel,Ryan;Heiny,Judith;Rubinstein,Jack;Koch,SherylE
通讯作者：
Koch,SherylE

Distinct α2 Na,K-ATPase membrane pools are differently involved in early skeletal muscle remodeling during disuse.

DOI：
10.1085/jgp.201511494
发表时间：
2016-02
期刊：
The Journal of general physiology
影响因子：
0
作者：
Kravtsova VV;Petrov AM;Matchkov VV;Bouzinova EV;Vasiliev AN;Benziane B;Zefirov AL;Chibalin AV;Heiny JA;Krivoi II
通讯作者：
Krivoi II

Metal ion transport quantified by ICP-MS in intact cells.