Role of the Extracellular Matrix in Age-Associated Strength Loss: Combining Imaging and Biochemistry to create a Multi-Scale Mesh-free Model

细胞外基质在与年龄相关的力量损失中的作用：结合成像和生物化学创建多尺度无网格模型

• 批准号: 9920653
• 负责人: Shantanu Sinha
• 金额: $ 64.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920653
• 关键词: Address; Adipose tissue; Adult; Affect; Age; Aged, 80 and over; Aging; American; Animals; Architecture; Area; Biochemical; Biochemistry; Biological Markers; Biology; Biopsy Specimen; Clinical; Computer Models; Connective Tissue; Contractile Proteins; Cross-Sectional Studies; Data; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Elderly; Electromyography; Equilibrium; Extracellular Matrix; Fatty acid glycerol esters; Fiber; Frail Elderly; Future; Goals; Grant; Healthcare Systems; Human; Hydroxyproline; Image; Immunochemistry; Immunohistochemistry; Immunoprecipitation; Impairment; Independent Living; Lateral; Life Expectancy; Link; Longevity; Magnetic Resonance Imaging; Maps; Measures; Metabolism; Methods; Modeling; Modification; Morphology; Mus; Muscle; Muscle Contraction; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Musculoskeletal; Nerve; Patients; Pattern; Phase; Population; Post-Translational Protein Processing; Process; Property; Proteins; Rehabilitation therapy; Rodent; Role; Ryanodine Receptor Calcium Release Channel; Sirius Red F3B; Statistical Models; Structure; Surface; Testing; Time; Water; Work; age related; aging population; base; bioimaging; clinical application; cohort; crosslink; exhaustion; frailty; gel electrophoresis; in vivo; indexing; muscle form; muscle strength; muscular structure; novel; prevent; rehabilitation paradigm; relating to nervous system; sarcopenia; skeletal muscle wasting; tool; transmission process; young adult

The overall goal of these studies is to elucidate the roles of different musculoskeletal factors in the loss of muscle quality with aging, with specific focus on the extracellular matrix (ECM). Sarcopenia, defined as age- associated loss of skeletal muscle mass, currently affects 50 million in the US with the number expected to rise to 200 million by 2050. The concomitant, disproportionately larger loss of muscle strength compared to size, termed dynopenia, cannot be accounted for completely by the widely believed primary causes, of neural and muscle contractility origin. Recent evidence from animal studies suggest that the ECM may be an important cause of loss of muscle quality since the more than 80% of force transmission occurring laterally through the ECM in young mice is significantly reduced in aging animals. The ECM remodels considerably with aging, in content, regional distribution, collagenous composition and cross-linking. However, the contribution of changes in the ECM to the loss of muscle quality in humans has never been investigated comprehensively. We hy- pothesize that altered lateral force transmission due to ECM remodeling contributes to dynopenia. A highly integrated array of MR imaging, neural activation, and biochemical and immuno-histochemical analysis on muscle biopsy samples, will be used to characterize the human plantar and dorsiflexor muscles in a cross-sectional study (N=30 each) of: (i) young (21-30 years) adults, (ii) active seniors (> 75 years) with min- imal dynopenia, and (iii) frail seniors (> 75 years) with significant dynopenia. To test the Hypothesis that dy- nopenia cannot be totally accounted for by decreases in muscle contractile quality, mass and neural drive, Specific Aim (SA)-1 will estimate the contributions of muscle and nerve to dynopenia by assessing age and frailty induced changes in (1) muscle mass, architecture using diffusion tensor MRI, material properties from dynamic MRI; (2) contractile quality based on ryanodine receptor modification, (3) fiber size using immu- nochemistry, and (4) muscle activation. To test the Hypothesis that ECM remodeling will account for the dis- crepancy identified in the SA-1, the contribution of ECM remodeling will be determined in SA-2 via quantifica- tion of (1) indices related to lateral transmission of force (shear strain, angle between the axis of shortening and muscle fiber from dynamic MRI), and (2) the content, orientation and composition of the ECM determined from MRI and cellular analysis. SA-3 will develop and validate a mesh-free multiscale (multi-cellular, compo- nent, and structural level) computational model, to establish mechanistic and causal links between subject- specific data from SA-1 and SA-2 to dynopenia with a focus on changes in lateral transmission of force. Such exhaustive characterization that targets all the major determinants of age-related force loss will enable us to (i) elucidate the role of ECM remodeling in dynopenia, (ii) identify surrogate imaging bio-markers for potential clinical applications, and (iii) assess the predictive power of the computational model to potentially inform the translational development of subject/ cohort-specific rehabilitative paradigms for a future RO1 grant.

这些研究的总体目标是阐明不同肌肉骨骼因素在损失中的作用 具有衰老的肌肉质量，特别关注细胞外基质（ECM）。肌肉减少症，被定义为年龄 骨骼肌质量的相关损失，目前在美国影响5000万，预计数量将增加 到2050年，到2050年。肌肉力量的肌肉力量损失与大小相比，肌肉力量的损失较大 被称为Dynopenia，无法完全由神经和神经的主要原因完全解释 肌肉收缩的起源。动物研究的最新证据表明，ECM可能是重要的 肌肉质量丧失的原因，因为超过80％的力传播横向发生 年轻小鼠的ECM在衰老动物中显着降低。 ECM随着衰老而进行大量重塑 内容，区域分布，胶原式组成和交联。但是，变化的贡献 在ECM中，从未对人类失去肌肉质量的丧失。我们 - 刺激了由于ECM重塑而改变的侧向力传播改变了dynopenia。 高度集成的MR成像，神经激活以及生化和免疫 - 归纳化学 分析肌肉活检样品，将用于表征人类足底和背屈肌肉 一项横断面研究（n = 30）的：（i）年轻（21-30岁）成年人，（ii）活跃的老年人（> 75年）， Imal dynopenia和（iii）弱年（> 75年），具有重要的dynopenia。测试dy-的假设 肌肉收缩质量降低，质量和神经驱动器的降低无法完全解释Nopenia 特定目标（SA）-1将通过评估年龄和 脆弱的（1）肌肉质量的变化，使用扩散张量MRI的结构，材料特性 动态MRI； （2）基于ryanonodine受体修饰的收缩质量，（3）纤维尺寸 Nochemistry和（4）肌肉激活。为了检验以下假设，即ECM重塑将解释 在SA-1中鉴定出的可爱，ECM重塑的贡献将在SA-2中通过量化确定 （1）与力横向传输有关的指标（剪切应变，缩短轴之间的角度 和动态MRI的肌肉纤维），以及（2）确定的ECM的含量，方向和组成 来自MRI和细胞分析。 SA-3将开发和验证无网格的多尺度（多细胞，组合 - NENT和结构级别）计算模型，以建立受试者之间的机械和因果关系 从SA-1和SA-2到Dynopenia的具体数据，重点是横向传输力的变化。 这种针对所有与年龄相关的力量损失的主要决定因素的详尽表征将 使我们能够（i）阐明ECM重塑在Dynopenia中的作用，（ii）识别替代成像生物标志物 对于潜在的临床应用，（iii）评估计算模型的预测能力 为未来的RO1赠款，告知主题/队列特定康复范式的翻译发展。