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Diaphragm muscle fibrosis involves changes in collagen organization with mechanical implications in Duchenne muscular dystrophy.

Authors:
Ridhi Sahani C Hunter Wallace Brian K Jones Silvia S Blemker

J Appl Physiol (1985) 2022 03 20;132(3):653-672. Epub 2022 Jan 20.

Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia.

In Duchenne muscular dystrophy (DMD), diaphragm muscle dysfunction results in respiratory insufficiency, a leading cause of death in patients. Increased muscle stiffness occurs with buildup of fibrotic tissue, characterized by excessive accumulation of extracellular matrix (ECM) components such as collagen, and prevents the diaphragm from achieving the excursion lengths required for respiration. However, changes in mechanical properties are not explained by collagen amount alone and we must consider the complex structure and mechanics of fibrotic tissue. The goals of our study were to ) determine if and how collagen organization changes with the progression of DMD in diaphragm muscle tissue and ) predict how collagen organization influences the mechanical properties of the ECM. We first visualized collagen structure with scanning electron microscopy (SEM) images and then developed an analysis framework to quantify collagen organization and generate image-based finite-element models. Image analysis revealed increased collagen fiber straightness and alignment in over wild type (WT) at 3 mo (straightness: = 0.976 ± 0.0108, WT = 0.887 ± 0.0309, alignment: = 0.876 ± 0.0333, WT = 0.759 ± 0.0416) and 6 mo (straightness: = 0.942 ± 0.0182, WT = 0.881 ± 0.0163, alignment: = 0.840 ± 0.0315, WT = 0.759 ± 0.0368). Collagen fibers retained a transverse orientation relative to muscle fibers (70°-90°) in all groups. Mechanical models predicted an increase in the transverse relative to longitudinal (muscle fiber direction) stiffness, with stiffness ratio (transverse/longitudinal) increased in over WT at 3 mo ( = 5.45 ± 2.04, WT = 1.97 ± 0.670) and 6 mo ( = 4.05 ± 0.985, WT = 1.96 ± 0.506). This study revealed changes in diaphragm ECM structure and mechanics during disease progression in the muscular dystrophy mouse phenotype, highlighting the need to consider the role of collagen organization on diaphragm muscle function. Scanning electron microscopy images of decellularized diaphragm muscle from WT and , Duchenne muscular dystrophy model, mice revealed that collagen fibers in the epimysium are oriented transverse to muscle fibers, with age- and disease-dependent changes in collagen arrangement. Finite-element models generated from these images predicted that changes in collagen arrangement during disease progression influence the mechanical properties of the extracellular matrix. Thus, changes in collagen fiber-level structure are implicated on tissue-level properties during fibrosis.

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http://dx.doi.org/10.1152/japplphysiol.00248.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076426PMC
March 2022

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