Influence of Innervation on Diaphragm Muscle Growth

神经支配对膈肌生长的影响

• 批准号: 7406024
• 负责人: Gary C. Sieck
• 金额: $ 31.18万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406024
• 关键词: Affect; Age; Area; Brain-Derived Neurotrophic Factor; Data; Denervation; Development; Excision; Family; Fiber; Figs - dietary; Genetic Transcription; Goals; Growth; Motor Neurons; Muscle; Muscle Fibers; Muscle denervation procedure; Myosin Heavy Chains; Nerve; Neurotrophic Tyrosine Kinase Receptor Type 2; Numbers; Play; Principal Investigator; Protein Biosynthesis; Protein Isoforms; Proteins; Rate; Rattus; Receptor Activation; Receptor Protein-Tyrosine Kinases; Regulation; Respiratory Diaphragm; Role; Sarcomeres; nerve supply; neurotrophic factor; neurotrophin 4; postnatal; programs; protein degradation; protein expression; size

DESCRIPTION (provided by applicant): During postnatal development, DIAm fibers display dramatic growth that is disproportionate across fibers expressing different myosin heavy chain (MHC) isoforms. Postnatal increase in specific force of DIAm fibers also varies across fibers expressing different MHC isoforms. Unilateral denervation (DNV) dramatically retards postnatal growth of DIAm fibers and reduces specific force. These data suggest that nerve-derived factors (such as the family of neurotrophins) play a key role in postnatal muscle fiber growth. We hypothesize that neurotrophins modulate the postnatal growth of DIAm fibers and MHC protein expression and thereby affect specific force. The major goals of the proposed studies are: 1) to explore the mechanisms regulating MHC protein expression during postnatal growth of DIAm fibers, 2) to explore the effects of TrkB receptor activation on MHC protein expression, 3) to explore the effects of DNV (i.e., removal of neurotrophin influence) on MHC protein expression, and 4) to examine the relationship between postnatal changes in MHC protein content and changes in specific force generated by DIAm fibers. There are four specific aims in the proposed studies: Specific Aim #1: To examine the impact of DNV on postnatal changes in myonuclear domain size in DIAm fibers Hypothesis la - Following DNV, myonuclear domain size decreases and this effect varies with postnatal age and across different MHC isoforms. Hypothesis lb - In cultured myotubes/myofibers, TrkB receptor activation increases myonuclear domain size. Specific Aim #2: To evaluate the impact of DNV on postnatal changes in MHC isoform transcription in DIAm fibers. Hypothesis 2a - Following DNV, MHC transcription decreases and this effect varies with postnatal age and across different MHC isoforms. Hypothesis 2b - In cultured myotubes/myofibers, TrkB receptor activation increases MHC transcription. Specific Aim #3: To evaluate the impact of DNV on postnatal changes in MHC protein content per haft sarcomere and MHC protein turnover in DIAm fibers. Hypothesis 3a - Following DNV, MHC protein content per half sarcomere decreases and this effect varies with postnatal age and across different MHC isoforms. Hypothesis 3b - Following DNV, the fractional synthesis rate of MHC decreases while degradation rate increases, and these effects on MHC turnover vary with postnatal age and across different MHC isoforms. Hypothesis 3c - In cultured myotubes/myofibers, TrkB receptor activation increases MHC protein expression. Specific Aim #4: To evaluate the impact of DNV on postnatal changes in specific force of DIAm fibers. Hypothesis 4a - Following DNV, specific force of DIAm fibers decreases and this effect varies with postnatal age and across fibers expressing different MHC isoforms. Hypothesis 4b - Following DNV, the decrease in DIAm fiber specific force reflects both a decrease in MHC content per half sarcomere and a decrease in the force per cross bridge.

描述（由申请人提供）：在出生后发育过程中，DIAm 纤维表现出急剧的生长，这种生长在表达不同肌球蛋白重链 (MHC) 亚型的纤维中不成比例。出生后 DIAm 纤维比力的增加在表达不同 MHC 同种型的纤维中也有所不同。单侧去神经术 (DNV) 会显着延缓 DIAm 纤维的出生后生长并降低比力。这些数据表明神经源性因子（例如神经营养素家族）在出生后肌纤维生长中发挥关键作用。我们假设神经营养素调节 DIAm 纤维的出生后生长和 MHC 蛋白表达，从而影响比力。拟议研究的主要目标是：1）探索DIAm纤维出生后生长过程中调节MHC蛋白表达的机制，2）探索TrkB受体激活对MHC蛋白表达的影响，3）探索DNV（即消除神经营养素的影响）对MHC蛋白表达的影响，4）检查出生后MHC蛋白变化之间的关系 DIAm 纤维的含量和比力的变化。拟议的研究有四个具体目标： 具体目标 #1：检查 DNV 对 DIAm 纤维中肌核结构域大小的出生后变化的影响 假设 la - DNV 后，肌核结构域大小减小，并且这种影响随出生后年龄和不同 MHC 亚型而变化。假设 lb - 在培养的肌管/肌纤维中，TrkB 受体激活会增加肌核结构域的大小。具体目标#2：评估 DNV 对 DIAm 纤维中 MHC 同工型转录的出生后变化的影响。假设 2a - DNV 后，MHC 转录减少，这种效应随出生后年龄和不同 MHC 亚型的不同而变化。假设 2b - 在培养的肌管/肌纤维中，TrkB 受体激活会增加 MHC 转录。具体目标#3：评估 DNV 对每个肌节 MHC 蛋白含量和 DIAm 纤维中 MHC 蛋白周转的出生后变化的影响。假设 3a - DNV 后，每半个肌节的 MHC 蛋白含量降低，这种效应随出生后年龄和不同 MHC 亚型的不同而变化。假设 3b - DNV 后，MHC 的合成率降低，而降解率增加，这些对 MHC 周转的影响随出生后年龄和不同 MHC 亚型的不同而变化。假设 3c - 在培养的肌管/肌纤维中，TrkB 受体激活增加 MHC 蛋白表达。具体目标#4：评估 DNV 对出生后 DIAm 纤维比力变化的影响。假设 4a - DNV 后，DIAm 纤维的比力降低，这种效应随出生后年龄以及表达不同 MHC 同工型的纤维而变化。假设 4b - DNV 之后，DIAm 纤维比力的下降反映了每半肌节 MHC 含量的下降和每个横桥力的下降。