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

这些研究的总体目标是阐明不同肌肉骨骼因素在丢失中的作用。 随着年龄的增长，肌肉质量的变化，特别是细胞外基质(ECM)。石棺减少症，定义为年龄- 相关的骨骼肌块丢失，目前在美国影响着5000万人，这个数字预计还会上升 到2050年达到2亿。随之而来的是，与体型相比，肌肉力量的损失不成比例地更大， 所谓的营养不良症，不能完全用普遍认为的神经和精神疾病的主要原因来解释 肌肉收缩的起源。最近来自动物研究的证据表明，ECM可能是一种重要的 肌肉质量丧失的原因，因为80%以上的力通过关节侧向传递 年轻小鼠的ECM在老年动物中显著减少。随着年龄的增长，ECM发生了相当大的变化 内容、地域分布、胶原蛋白组成和交联度。然而，变化的贡献 在ECM中，对人类肌肉质量的丧失从未进行过全面的研究。我们- 由于ECM重塑改变了侧向力传递，导致营养不良。 一个高度集成的磁共振成像、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，将被用来描述人类足底和背屈肌的特征 一项横断面研究(N=30)：(I)年轻人(21-30岁)，(Ii)活跃的老年人(75岁)。 IMAL营养不良，以及(Iii)虚弱的老年人(75岁)有明显的营养不良。来检验这个假设-- 肌肉收缩质量、质量和神经驱动力的下降不能完全解释肌肉缺乏的原因， 特异性目标(SA)-1将通过评估年龄和年龄来评估肌肉和神经对营养不良的贡献 脆弱引起的变化(1)肌肉质量，使用扩散张量磁共振成像的结构，材料特性来自 动态磁共振成像；(2)基于兰尼定受体修饰的收缩质量；(3)利用免疫球蛋白测定纤维大小。 非化学作用；(4)肌肉激活。为了检验ECM重塑将解释这种差异的假设 在SA-1中确定的可信度，ECM重塑的贡献将在SA-2中通过定量- (1)与横向传力有关的指标(剪切应变、缩短轴夹角 和来自动态MRI的肌纤维)，以及(2)确定ECM的含量、取向和组成 来自核磁共振和细胞分析。SA-3将开发和验证无网格多尺度(多细胞，复合 Nent和Structure Level)计算模型，以建立主体之间的机械联系和因果联系 从SA-1和SA-2到营养不良的具体数据，重点是力量横向传递的变化。 这种针对与年龄相关的部队损失的所有主要决定因素的详尽描述将 使我们能够(I)阐明细胞外基质重塑在营养不良中的作用，(Ii)确定替代成像生物标志物 用于潜在的临床应用，以及(Iii)评估计算模型的预测能力 为未来RO1奖助金的主题/队列特定的康复范例的翻译开发提供信息。

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.