Background

In human skeletal muscles, the aging process causes a decrease of contractile and a concomitant increase of intramuscular adipose (IMAT) and connective (IMCT) tissues. The accumulation of non-contractile tissues may contribute to the significant loss of intrinsic muscle strength typically observed at older age but their in vivo quantification is challenging. The purpose of this study was to establish MR imaging-based methods to quantify the relative amounts of IMCT, IMAT and contractile tissues in young and older human cohorts, and investigate their roles in determining age-associated changes in skeletal muscle strength.

Methods

Five young (31.6 ± 7.0 yrs) and five older (83.4 ± 3.2 yrs) Japanese women were subject to a detailed MR imaging protocol, including Fast Gradient Echo, Quantitative Fat/Water (IDEAL) and Ultra-short Echo Time (UTE) sequences, to determine contractile muscle tissue and IMAT within the entire Triceps Surae complex, and IMCT within both heads of the Gastrocnemius muscle. Specific force was calculated as the ratio of isometric plantarflexor force and the physiological cross-sectional area of the Triceps Surae complex.

Results

In the older cohort, total Triceps Surae volume was smaller by 17.5%, while the relative amounts of Triceps Surae IMAT and Gastrocnemius IMCT were larger by 55.1% and 48.9%, respectively. Differences of 38.6% and 42.1% in plantarflexor force and specific force were observed. After subtraction of IMAT and IMCT from total muscle volume, differences in intrinsic strength decreased to 29.6%.

Conclusions

Our data establishes that aging causes significant changes in skeletal muscle composition, with marked increases in non-contractile tissues. Such quantification of the remodeling process is likely to be of functional and clinical importance in elucidating the causes of the disproportionate age-associated decrease of force compared to that of muscle volume.

The focus of this review is the application of advanced MRI to study the effect of aging and disuse related remodeling of the extracellular matrix (ECM) on force transmission in the human musculoskeletal system. Structural MRI includes (i) ultra-low echo times (UTE) maps to visualize and quantify the connective tissue, (ii) diffusion tensor imaging (DTI) modeling to estimate changes in muscle and ECM microstructure, and (iii) magnetization transfer contrast imaging to quantify the macromolecular fraction in muscle. Functional MRI includes dynamic acquisitions during contraction cycles enabling computation of the strain tensor to monitor muscle deformation. Further, shear strain extracted from the strain tensor may be a potential surrogate marker of lateral transmission of force. Biochemical and histological analysis of muscle biopsy samples can provide "gold-standard" validation of some of the MR findings. The review summarizes biochemical studies of ECM adaptations with age and with disuse. A brief summary of animal models is included as they provide experimental confirmation of longitudinal and lateral force transmission pathways. Computational muscle models enable exploration of force generation and force pathways and elucidate the link between structural adaptations and functional consequences. MR image findings integrated in a computational model can explain and predict subject specific functional changes to structural adaptations. Future work includes development and validation of MRI biomarkers using biochemical analysis of muscle tissue as a reference standard and potential translation of the imaging markers to the clinic to noninvasively monitor musculoskeletal disease conditions and changes consequent to rehabilitative interventions.

Muscle force production is influenced by muscle fiber and aponeurosis architecture. This prospective cohort study utilizes special MR imaging sequences to examine the structure-function in-vivo in the Medial Gastrocnemius (MG) at three-ankle angles (dorsiflexion, plantar flexion-low and high) and two sub-maximal levels of maximum voluntary contraction (25% and 50%MVC). The study was performed on 6 young male participants. Muscle fiber and aponeurosis strain, fiber strain normalized to force, fiber length and pennation angle (at rest and peak contraction) were analyzed for statistical differences between ankle positions and %MVC. A two-way repeated measures ANOVA and post hoc Bonferroni-adjusted tests were conducted for normal data. A related samples test with Friedmans 2-way ANOVA by ranks with corrections for multiple comparisons was conducted for non-normal data. The dorsiflexed ankle position generated significantly higher force with lower fiber strain than the plantarflexed positions. Sarcomere length extracted from muscle fiber length at each ankle angle was used to track the location on the Force-Length curve and showed the MG operates on the curves ascending limb. Muscle force changes predicted from the F-L curve going from dorsi- to plantarflexion was less than that experimentally observed suggesting other determinants of force changes with ankle position.

PURPOSE: Implement STEAM-DTI to model time-dependent diffusion eigenvalues using the random permeable barrier model (RPBM) to study age-related differences in the medial gastrocnemius (MG) muscle. Validate diffusion model-extracted fiber diameter for histological assessment. METHODS: Diffusion imaging at different diffusion times (Δ) was performed on seven young and six senior participants. Time-dependent diffusion eigenvalues (λ2 (t), λ3 (t), and D⊥ (t); average of λ2 (t) and λ3 (t)) were fit to the RPBM to extract tissue microstructure parameters. Biopsy of the MG tissue for histological assessment was performed on a subset of participants (four young, six senior). RESULTS: λ3 (t) was significantly higher in the senior cohort for the range of diffusion times. RPBM fits to λ2 (t) yielded fiber diameters in agreement to those from histology for both cohorts. The senior cohort had lower values of volume fraction of membranes, ζ, in fits to λ2 (t), λ3 (t), and D⊥ (t) (significant for fit to λ3 (t)). Fits of fiber diameter from RPBM to that from histology had the highest correlation for the fit to λ2 (t). CONCLUSION: The age-related patterns in λ2 (t) and λ3 (t) could tentatively be explained from RPBM fits; these patterns may potentially arise from a decrease in fiber asymmetry and an increase in permeability with age.

Human aging results in a progressive decline in the active force generation capability of skeletal muscle. While many factors related to the changes of morphological and structural properties in muscle fibers and the extracellular matrix (ECM) have been considered as possible reasons for causing age-related force reduction, it is still not fully understood why the decrease in force generation under eccentric contraction (lengthening) is much less than that under concentric contraction (shortening). Biomechanically, it was observed that connective tissues (endomysium) stiffen as ages, and the volume ratio of connective tissues exhibits an age-related increase. However, limited skeletal muscle models take into account the microstructural characteristics as well as the volume fraction of tissue material. This study aims to provide a numerical investigation in which the muscle fibers and the ECM are explicitly represented to allow quantitative assessment of the age-related force reduction mechanism. To this end, a fiber-level honeycomb-like microstructure is constructed and modeled by a pixel-based Reproducing Kernel Particle Method (RKPM), which allows modeling of smooth transition in biomaterial properties across material interfaces. The numerical investigation reveals that the increased stiffness of the passive materials of muscle tissue reduces the force generation capability under concentric contraction while maintains the force generation capability under eccentric contraction. The proposed RKPM microscopic model provides effective means for the cellular-scale numerical investigation of skeletal muscle physiology. NOVELTY STATEMENT: A cellular-scale honeycomb-like microstructural muscle model constructed from a histological cross-sectional image of muscle is employed to study the causal relations between age-associated microstructural changes and age-related force loss using Reproducing Kernel Particle Method (RKPM). The employed RKPM offers an effective means for modeling biological materials based on pixel points in the medical images and allow modeling of smooth transition in the material properties across interfaces. The proposed microstructure-informed muscle model enables quantitative evaluation on how cellular-scale compositions contribute to muscle functionality and explain differences in age-related force changes during concentric, isometric and eccentric contractions.

This paper introduces the meshfree Reproducing Kernel Particle Method (RKPM) for 3D image-based modeling of skeletal muscles. This approach allows for construction of simulation model based on pixel data obtained from medical images. The material properties and muscle fiber direction obtained from Diffusion Tensor Imaging (DTI) are input at each pixel point. The reproducing kernel (RK) approximation allows a representation of material heterogeneity with smooth transition. A multiphase multichannel level set based segmentation framework is adopted for individual muscle segmentation using Magnetic Resonance Images (MRI) and DTI. The application of the proposed methods for modeling the human lower leg is demonstrated.