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的肌肉骨骼因素在损失中的作用 随着年龄的增长，肌肉质量，特别是细胞外基质（ECM）。肌肉减少症，定义为年龄- 与之相关的骨骼肌质量损失，目前在美国影响着5000万人，预计这一数字还会上升 到2050年达到2亿伴随而来的，与体型相比，肌肉力量的损失不成比例地更大， 被称为动力性，不能完全解释为广泛认为的主要原因，神经和 肌肉收缩力来源。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%的力传递发生横向通过 年轻小鼠中的ECM在老龄动物中显著减少。ECM随着老化而显著重塑， 含量、区域分布、胶原成分和交联。然而，变化的贡献 在ECM中的肌肉质量的损失在人类中从未被全面调查。我们- 推测ECM重塑导致的侧向力传递改变有助于动力学改变。 磁共振成像、神经激活、生化和免疫组织化学的高度集成阵列 肌肉活检样本的分析，将用于表征人类足底和背屈肌肌肉， 一项横断面研究（N=30）：（i）年轻（21-30岁）成人，（ii）活跃的老年人（> 75岁）， 肌力异常，和（iii）虚弱的老年人（> 75岁）有显着的肌力异常。为了验证这个假设- 疼痛不能完全由肌肉收缩质量、质量和神经驱动的降低来解释， 特异性目标（SA）-1将通过评估年龄来估计肌肉和神经对肌力的贡献， 虚弱引起的（1）肌肉质量、使用扩散张量MRI的结构、 动态MRI;（2）基于ryanodine受体修饰的收缩质量，（3）使用免疫组织化学的纤维尺寸， 非化学，和（4）肌肉激活。为了验证ECM重塑将解释这种疾病的假设， SA-1中识别出的差异，将在SA-2中通过定量确定ECM重塑的贡献- （1）与力的横向传递有关的指标（剪切应变、缩短轴之间的角度 和来自动态MRI的肌纤维），和（2）测定的ECM的含量、取向和组成 核磁共振成像和细胞分析SA-3将开发和验证一个无网格多尺度（多细胞，复合， 内容和结构水平）计算模型，以建立主体之间的机械和因果联系， 从SA-1和SA-2到dynoderm的具体数据，重点关注力的横向传递变化。 这种针对与年龄相关的力损失的所有主要决定因素的详尽表征将 使我们能够（i）阐明ECM重塑在动力学中的作用，（ii）识别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，以潜在地 为未来的RO 1赠款提供主题/群体特定康复范例的翻译发展信息。

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.