Muscle fibrosis due to loss of desmin increases muscle stiffness due to an increased number of perimysial collagen cables (1102.8)

Abstract

Skeletal muscle stiffness increases with injury and disease, yet the structural basis of stiffness is unknown. The purpose of this study was to quantify perimysial collagen in a model of skeletal muscle fibrosis (desmin knockout, des‐/‐) to determine if increased stiffness correlates with increased volume fraction of these structures. Stereology was performed on mouse 5th toe extensor digitorum longus (EDL) muscles to quantify perimysial collagen volume fraction and mechanical testing was performed to determine muscle stress at incremental sarcomere lengths. Stereology indicated a significantly higher volume fraction of collagen fibrils in cables in des‐/‐ compared to wt (Table 1). Tangent stiffness of des‐/‐ compared to wt (Fig. 1) was four times greater (p<0.05). In des‐/‐ muscle, perimysial collagen cable volume increased concurrent with stiffness while no increase was observed in endomysial collagen, implicating the perimysial collagen structures in increased stiffness at the whole muscle level, not just increased collagen in general. These results suggest that therapies targeting perimysial collagen cables may improve function in fibrotic skeletal muscle. Table 1. Volume fraction of muscle components as percent EDL volume. Mean ± SEM, *p<0.05. Muscle Component Wild type (n = 8) Desmin knockout (n = 8) Myofibrils 59.2 ± 2.4 59.2 ± 2.8 Mitochondria 9.53 ± 0.8 8.20 ± 1.0 Myonuclei 0.55 ± 0.07 0.78 ± 0.13 Satellite cells 0.02 ± 0.009 0.009 ± 0.009 Fibroblasts 0.59 ± 0.14 0.74 ± 0.11 Single collagen fibrils 1.51 ± 0.31 1.26 ± 0.13 Collagen fibrils in cable 2.45 ± 0.26 4.15 ± 0.55* Basement membrane 2.18 ± 0.23 1.83 ± 0.08