The Sarcoglycan Complex in Skeletal Muscle Mechanotransduction

骨骼肌机械转导中的肌聚糖复合物

• 批准号: 9247122
• 负责人: Elisabeth R Barton
• 金额: $ 39.04万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247122
• 关键词: Ablation; Acute; Affect; Binding; Biochemical; Cancer Etiology; Cell Nucleus; Cells; Cellular Mechanotransduction; Clinical Trials; Complex; Defect; Disease; Dissection; Down-Regulation; Drug usage; Duchenne muscular dystrophy; Dystrophin; Event; Focal Adhesions; Future; GTP-Binding Protein alpha Subunits, Gs; Genes; Health; Human; Lead; Limb-Girdle Muscular Dystrophies; MAPK3 gene; Mechanics; Mediating; Membrane; Modeling; Molecular; Mus; Muscle; Muscle Contraction; Muscle Fibers; Muscle function; Muscle strain; Muscular Atrophy; Muscular Dystrophies; Myopathy; Myosin Type II; Nature; Neuromuscular Diseases; Nuclear; Pathologic; Pathology; Pathway interactions; Patients; Phosphorylation; Physical activity; Positioning Attribute; Predisposition; Property; Protein Isoforms; Protein Splicing; Proteins; Research; Rest; Role; Sarcoglycans; Sarcolemma; Signal Pathway; Signal Transduction; Skeletal Muscle; Stimulus; Stretching; Therapeutic; Work; base; filamin; gamma Sarcoglycan; improved; knock-down; mdx mouse; mechanical load; mechanotransduction; muscle degeneration; mutant; non-muscle myosin; normal aging; novel; novel strategies; novel therapeutics; protein expression; public health relevance; response; sensor; small hairpin RNA; therapeutic development

 DESCRIPTION (provided by applicant): Physical activity imposes changes in load to skeletal muscle, which adapts through acute changes in biochemical signaling pathways and longer-term alterations in protein expression. One important mechanical sensor is the sarcoglycan (SG) complex, which is lost from the muscle membrane (sarcolemma) in both Duchenne and Limb Girdle muscular dystrophies (LGMD). Absence of γ-SG loss induces severe muscle degeneration and signaling defects in response to mechanical load without causing susceptibility to contractile damage, suggesting that LGMD pathology arises in part through disruption of normal mechanotransduction signaling through the SG complex. In a recent advance, the applicants have discovered that archvillin, a muscle-specific isoform of supervillin, is a γ-SG- and dystrophin-interacting protein and that archvillin association with phosphorylated ERK1/2 (P-ERK) increases dramatically, if and only if γ-SG is present, following eccentric contraction of muscle. Aim 1 is to determine the molecular bases for the associations of archvillin with γ-SG and P-ERK at rest and following stretch. Aim 2 is to determine the consequences of archvillin loss upon mechanical signal transduction in normal and dystrophic muscles. Aim 3 is to use drugs in clinical trials for other diseases to determine how up- or down-regulation of the molecular pathways identified in preliminary studies and in Aim 1 affects the progression of muscle pathology in gsg-/- mice, a model for human LGMD2C. Completion of these aims will elucidate the role of archvillin in mechanochemical signal transduction in muscle, identify new proteins in SG-mediated signaling, and determine whether modulation of the identified pathways has therapeutic potential.

 描述(申请人提供)：体力活动对骨骼肌施加负荷的变化，骨骼肌通过生化信号通路的急剧变化和蛋白质表达的长期变化来适应。一个重要的机械感受器是肌聚糖(SG)复合体，在Duchenne和Limb Girdle肌营养不良症(LGMD)中，它从肌膜(肌膜)中消失。γ-SG缺失可导致严重的肌肉变性和信号缺陷，以响应机械负荷，而不会导致收缩损伤易感性，提示LGMD病理部分是通过破坏通过SG复合体的正常机械转导信号而发生的。在最近的进展中，申请人发现，超级绒毛蛋白的一种肌肉特异性亚型，是一种与γ-SG和dystrophin相互作用的蛋白质，并且当且仅当γ-SG存在时，随着肌肉的偏心收缩，与磷酸化ERK1/2(P-ERK1/2)相关的蛋白显著增加。目的1是确定γ-SG和P-ERK在静息和牵张后结合的分子基础。目的2是确定拱毛蛋白缺失对正常和营养不良肌肉的机械信号转导的影响。目标3是将药物用于其他疾病的临床试验，以确定在初步研究和目标1中确定的分子通路的上调或下调如何影响GSG-/-小鼠肌肉病理的进展，GSG-/-小鼠是人类LGMD2C的模型。这些目标的完成将阐明ARCHVILIN在肌肉机械力化学信号转导中的作用，识别SG介导的信号转导中的新蛋白质，并确定对已识别的信号通路的调制是否具有治疗潜力。