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: 10398870
• 负责人: Shantanu Sinha
• 金额: $ 54.94万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398870
• 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; Persons; Phase; Population; Post-Translational Protein Processing; Process; Property; Proteins; Rehabilitation therapy; Rodent; Role; Ryanodine Receptor Calcium Release Channel; Sirius Red F3B; Statistical Models; Surface; Testing; Time; Water; Work; age related; aging population; base; bioimaging; clinical application; cohort; crosslink; exhaustion; frailty; gel electrophoresis; in vivo; indexing; multi-scale modeling; 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 肌肉质量随衰老的变化，特别关注细胞外基质 (ECM)。肌肉减少症，定义为年龄- 相关的骨骼肌质量损失，目前影响美国 5000 万人，预计这一数字还会上升 到 2050 年，这一数字将增至 2 亿。随之而来的，与体型相比，肌肉力量的损失要大得多， 被称为减少症，不能完全用广泛认为的神经和神经系统疾病的主要原因来解释。 肌肉收缩力的起源。最近的动物研究证据表明 ECM 可能是一个重要的 肌肉质量损失的原因，因为超过 80% 的力传递发生在横向上 年轻小鼠的 ECM 在衰老动物中显着降低。 ECM 随着衰老而发生显着重塑， 含量、区域分布、胶原成分和交联。然而，变化的贡献 ECM 对人类肌肉质量损失的影响从未得到过全面的研究。我们嘿- 假设 ECM 重塑改变侧向力传递会导致细胞减少。 高度集成的 MR 成像、神经激活、生化和免疫组织化学阵列 对肌肉活检样本的分析将用于表征人类足底和背屈肌 一项横断面研究（每项 N = 30）：(i) 年轻人（21-30 岁）成年人，(ii) 活跃的老年人（> 75 岁），年龄最小 动物缺乏症，以及 (iii) 体弱的老年人（> 75 岁），患有明显的缺乏症。检验假设 肌肉萎缩不能完全用肌肉收缩质量、质量和神经驱动力的下降来解释， 具体目标 (SA)-1 将通过评估年龄和肌肉和神经对缺乏症的贡献来估计 虚弱引起的变化 (1) 肌肉质量、使用扩散张量 MRI 的结构、材料特性 动态磁共振成像； (2) 基于兰尼碱受体修饰的收缩质量，(3) 使用免疫的纤维尺寸 无化学反应，以及（4）肌肉激活。为了检验 ECM 重塑将解释该问题的假设 SA-1 中确定的裂纹，ECM 重塑的贡献将在 SA-2 中通过定量确定 (1) 与力的横向传递相关的指标（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 的内容、方向和成分 来自 MRI 和细胞分析。 SA-3 将开发和验证无网格多尺度（多细胞、复合材料） nent和结构水平）计算模型，以建立主题之间的机械和因果联系 从 SA-1 和 SA-2 到缺乏减少的具体数据，重点是力的横向传递的变化。 这种针对与年龄相关的力量损失的所有主要决定因素的详尽描述将 使我们能够 (i) 阐明 ECM 重塑在减少症中的作用，(ii) 识别替代成像生物标志物 潜在的临床应用，以及（iii）评估计算模型的预测能力 为未来 RO1 拨款的主题/队列特定康复范例的转化发展提供信息。

项目成果

Myofibrillar protein synthesis rates are increased in chronically exercised skeletal muscle despite decreased anabolic signaling.

• DOI: 10.1038/s41598-022-11621-x
• 发表时间: 2022-05-09
• 期刊: Scientific reports
• 影响因子: 4.6

Magnetic resonance imaging based muscle strain rate mapping during eccentric contraction to study effects of unloading induced by unilateral limb suspension.

基于磁共振成像的偏心收缩期间的肌肉应变率图，以研究单侧肢体悬挂引起的卸载效果。

• DOI: 10.4081/ejtm.2019.8935
• 发表时间: 2020
• 期刊: European journal of translational myology
• 影响因子: 2.2
• 作者: Sinha,Usha;Malis,Vadim;Csapo,Robert;Narici,Marco;Sinha,Shantanu
• 通讯作者: Sinha,Shantanu

Investigating the Correlation between Force Output, Strains, and Pressure for Active Skeletal Muscle Contractions.

研究主动骨骼肌收缩的力输出、应变和压力之间的相关性。

• 发表时间: 2023
• 期刊: ArXiv
• 作者: Taneja,Karan;He,Xiaolong;Hodgson,John;Sinha,Usha;Sinha,Shantanu;Chen,JS
• 通讯作者: Chen,JS

A Feature-Encoded Physics-Informed Parameter Identification Neural Network for Musculoskeletal Systems.

• DOI: 10.1115/1.4055238
• 发表时间: 2022-12-01
• 期刊: JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME
• 影响因子: 1.7
• 作者: Taneja, Karan;He, Xiaolong;He, QiZhi;Zhao, Xinlun;Lin, Yun-An;Loh, Kenneth J.;Chen, Jiun-Shyan
• 通讯作者: Chen, Jiun-Shyan

Microstructural analysis of skeletal muscle force generation during aging.

• DOI: 10.1002/cnm.3295
• 发表时间: 2020-01
• 期刊: International journal for numerical methods in biomedical engineering
• 影响因子: 2.1
• 作者: Zhang Y;Chen JS;He Q;He X;Basava RR;Hodgson J;Sinha U;Sinha S
• 通讯作者: Sinha S