A 3D mesomechanical modeling framework for skeletal muscle: Influence of fascicle architecture and ECM volume on mechanical behavior

Skeletal muscle exhibits a hierarchical and heterogeneous architecture in which fascicles and their surrounding extracellular matrix (ECM) compose the interplay of biomechanical functions. While experimental studies indicate that muscle morphology — comprising ECM content and fascicle architecture — influences muscle mechanics, the direct contributions of these mesoscale features remain poorly quantified. Here, we develop a mesoscale finite element framework to investigate how fascicle number and ECM volume fraction affect passive and active muscle responses. Representative volume elements were generated using centroidal Voronoi tessellation with Lloyd's method, combined with a customized algorithm to replicate fascicle–ECM geometries. Parametric variations spanned fascicle counts from 15 to 70 and ECM ratios from 2% (healthy) to 20% (fibrotic or aged), covering physiological and pathological ranges. Simulation results revealed that active peak stresses remained stable across configurations (∼0.85 MPa at 10% elongation) with less than 1% variability, whereas passive responses were highly sensitive to ECM fraction. Increasing ECM content reduced passive stiffness and altered fascicle–ECM load sharing, with up to 8.36% variability across the evaluated range. Reaction force analyses demonstrated that excessive ECM, fibrosis or aging, amplifies load carried by connective tissue, potentially impairing force transmission. Global stress transmission in both active and passive states showed a notable trend with ECM ratio: average stress at the functional surface relates inversely to ECM presence, particularly under active conditions. The framework links mesoscale heterogeneity to macroscopic function, bridging a critical gap in skeletal muscle modeling, with potential extensions to multiscale models of adaptation, degeneration, and therapeutic intervention.