Delayed skeletal muscle repair following inflammatory damage in simulated agent-based models of muscle regeneration.

Healthy skeletal muscle undergoes repair in response to mechanically localised strains during activities such as exercise. The ability of cells to transduce the external stimuli into a cascade of cell signalling responses is important to the process of muscle repair and regeneration. In chronic myopathies such as Duchenne muscular dystrophy and inflammatory myopathies, muscle is often subject to chronic necrosis and inflammation that perturbs tissue homeostasis and leads to non-localised, widespread damage across the tissue. Here we present an agent-based model that simulates muscle repair in response to both localised eccentric contractions similar to what would be experienced during exercise, and non-localised widespread inflammatory damage that is present in chronic disease. Computational modelling of muscle repair allows for in silico exploration of phenomena related to muscle disease. In our model, widespread inflammation led to delayed clearance of tissue damage, and delayed repair for recovery of initial fibril counts at all damage levels. Macrophage recruitment was delayed and significantly higher in widespread compared to localised damage. At higher damage percentages of 10%, widespread damage led to impaired muscle regeneration and changes in muscle geometry that represented alterations commonly observed in chronic myopathies, such as fibrosis. This computational work offers insight into the progression and aetiology of inflammatory muscle diseases, and suggests a focus on the muscle regeneration cascade in understanding the progression of muscle damage in inflammatory myopathies

Muscle architecture, growth, and biological Remodelling in cerebral palsy: a narrative review

Cerebral palsy (CP) is caused by a static lesion to the brain occurring in utero or up to the first 2 years of life; it often manifests as musculoskeletal impairments and movement disorders including spasticity and contractures. Variable manifestation of the pathology across individuals, coupled with differing mechanics and treatments, leads to a heterogeneous collection of clinical phenotypes that affect muscles and individuals differently. Growth of muscles in CP deviates from typical development, evident as early as 15 months of age. Muscles in CP may be reduced in volume by as much as 40%, may be shorter in length, present longer tendons, and may have fewer sarcomeres in series that are overstretched compared to typical. Macroscale and functional deficits are likely mediated by dysfunction at the cellular level, which manifests as impaired growth. Within muscle fibres, satellite cells are decreased by as much as 40–70% and the regenerative capacity of remaining satellite cells appears compromised. Impaired muscle regeneration in CP is coupled with extracellular matrix expansion and increased pro-inflammatory gene expression; resultant muscles are smaller, stiffer, and weaker than typical muscle. These differences may contribute to individuals with CP participating in less physical activity, thus decreasing opportunities for mechanical loading, commencing a vicious cycle of muscle disuse and secondary sarcopenia. This narrative review describes the effects of CP on skeletal muscles encompassing substantive changes from whole muscle function to cell-level effects and the effects of common treatments. We discuss growth and mechanics of skeletal muscles in CP and propose areas where future work is needed to understand these interactions, particularly the link between neural insult and cell-level manifestation of CP.</p

Soleus muscle weakness in cerebral palsy: Muscle architecture revealed with Diffusion Tensor Imaging.

Cerebral palsy (CP) is associated with movement disorders and reduced muscle size. This latter phenomenon has been observed by computing muscle volumes from conventional MRI, with most studies reporting significantly reduced volumes in leg muscles. This indicates impaired muscle growth, but without knowing muscle fiber orientation, it is not clear whether muscle growth in CP is impaired in the along-fiber direction (indicating shortened muscles and limited range of motion) or the cross-fiber direction (indicating weak muscles and impaired strength). Using Diffusion Tensor Imaging (DTI) we can determine muscle fiber orientation and construct 3D muscle architectures which can be used to examine both along-fiber length and cross-sectional area. Such an approach has not been undertaken in CP. Here, we use advanced DTI sequences with fast imaging times to capture fiber orientations in the soleus muscle of children with CP and age-matched, able-bodied controls. Cross sectional areas perpendicular to the muscle fiber direction were reduced (37 ± 11%) in children with CP compared to controls, indicating impaired muscle strength. Along-fiber muscle lengths were not different between groups. This study is the first to demonstrate along-fiber and cross-fiber muscle architecture in CP using DTI and implicates impaired cross-sectional muscle growth in children with cerebral palsy

Correction: Soleus muscle weakness in cerebral palsy: Muscle architecture revealed with Diffusion Tensor Imaging.

[This corrects the article DOI: 10.1371/journal.pone.0205944.]

Determining skeletal muscle architecture with Laplacian simulations: a comparison with diffusion tensor imaging

Determination of skeletal muscle architecture is important for accurately modeling muscle behavior. Current methods for 3D muscle architecture determination can be costly and time-consuming, making them prohibitive for clinical or modeling applications. Computational approaches such as Laplacian flow simulations can estimate muscle fascicle orientation based on muscle shape and aponeurosis location. The accuracy of this approach is unknown, however, since it has not been validated against other standards for muscle architecture determination. In this study, muscle architectures from the Laplacian approach were compared to those determined from diffusion tensor imaging in eight adult medial gastrocnemius muscles. The datasets were subdivided into training and validation sets, and computational fluid dynamics software was used to conduct Laplacian simulations. In training sets, inputs of muscle geometry, aponeurosis location, and geometric flow guides resulted in good agreement between methods. Application of the method to validation sets showed no significant differences in pennation angle (mean difference 0.5 ∘) or fascicle length (mean difference 0.9 mm). Laplacian simulation was thus effective at predicting gastrocnemius muscle architectures in healthy volunteers using imaging-derived muscle shape and aponeurosis locations. This method may serve as a tool for determining muscle architecture in silico and as a complement to other approaches.</p

Nomenclature of the tendon hierarchy: An overview of inconsistent terminology and a proposed size-based naming scheme with terminology for multi-muscle tendons.

Letter to the Edito

Spatial and age-related changes in the microstructure of dystrophic and healthy diaphragms

<div><p>Duchenne muscular dystrophy (DMD) is a progressive degenerative disease that results in fibrosis and atrophy of muscles. The main cause of death associated with DMD is failure of the diaphragm. The diaphragm is a dome-shaped muscle with a fiber microstructure that differs across regions of the muscle. However, no studies to our knowledge have examined spatial variations of muscle fibers in dystrophic diaphragm or how aging affects those variations in DMD. In this study, diaphragms were obtained from <i>mdx</i> and healthy mice at ages three, seven, and ten months in the dorsal, midcostal, and ventral regions. Through immunostaining and confocal imaging, we quantified sarcomere length, interstitial space between fibers, fiber branching, fiber cross sectional area (CSA), and fiber regeneration measured by centrally located nuclei. Because DMD is associated with chronic inflammation, we also investigated the number of macrophages in diaphragm muscle cross-sections. We saw regional differences in the number of regenerating fibers and macrophages during the progression of DMD in the <i>mdx</i> diaphragm. Additionally, the number of regenerating fibers increased with age, while CSA and the number of branching fibers decreased. Dystrophic diaphragms had shorter sarcomere lengths than age-matched controls. Our results suggest that the dystrophic diaphragm in the <i>mdx</i> mouse is structurally heterogeneous and remodels non-uniformly over time. Understanding regional changes in dystrophic diaphragms over time will facilitate the development of targeted therapies to prevent or minimize respiratory failure in DMD patients.</p></div

Healthy and dystrophic diaphragms are regionally diverse.

<p>(A, C, E): CSA, the percentage of regenerating fibers and macrophages exhibit spatial variations. Dystrophic diaphragms have a greater percentage of regenerating fibers and macrophages and smaller CSAs than controls. * = P<0.05 compared to dorsal, φ = P<0.05 compared to midcostal. (B, D, F): Regional differences in microstructure are altered with age. In three and ten month old <i>mdx</i> mice, the number of macrophages is increased in the midcostal region compared with the ventral and dorsal region. The number of regenerating fibers increases with age in the ventral region in <i>mdx</i> diaphragms. * = P<0.05 compared to three months, φ = P<0.05 compared to seven months. D, M, V: dorsal, midcostal, and ventral regions. Values are means ± SD.</p

<i>Mdx</i> diaphragms have greater interstitial space and more branched fibers than healthy diaphragms.

<p>Representative confocal images (60x objective) of sarcomere length, interstitial space, and branched fibers in diaphragms from 3, 7, and 10 month old <i>mdx</i> and healthy mice in the dorsal, midcostal, and ventral regions (red = alpha-actinin). Bar = 25 μm.</p

<i>Mdx</i> diaphragms exhibit a clear progression of muscular dystrophy as mice age.

<p>(A, C, E): Sarcomere length, the interstitial space ratio, and the percent of branched fibers are spatially heterogeneous in both the healthy and dystrophic diaphragm. Dystrophic diaphragms have shorter sarcomeres and more interstitial space and branched fibers than control mice. * = P<0.05 compared to dorsal, φ = P<0.05 compared to midcostal. (B, D, F): Regional differences in diaphragm microstructure are altered with age. Interstitial space varies with age, whereas the percent of branched fibers decreases with age in healthy and dystrophic diaphragms. * = P<0.05 compared to three months, φ = P<0.05 compared to seven months. D, M, V: dorsal, midcostal, and ventral regions. Values are means ± SD.</p