Altered composition, structure of muscles linked to stiffness, movement limits in CP children

Muscle composition and structure is altered in children with cerebral palsy — with greater amounts of collagen in the muscles’ network of proteins and sugars — making these patients more prone to stiffness and contractures that prevent normal movement, a study finds. The study was published in the journal Connective Tissue Research.

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By Ana Pena PhD, Cerebral Palsy News Today December 9, 2019

Joint contractures in children with cerebral palsy (CP), which affect range of motion and cause pain, are a highly disabling problem for which current treatments have limited efficacy.

When muscles or tendons remain too tight for too long, contractures occur, resulting in a shortening of these tissues. Contractures develop when otherwise normally elastic tissues are replaced by inelastic, fiber-like tissue, which make it hard to stretch the area.

The muscles of children with CP are stiffer than normal and endure greater strain, which contributes to the formation of contractures and prevents normal movement. Yet, the exact reason why this happens remains unknown. Prior research has shown no differences in the rigidity of individual muscle cells between patients with CP and healthy people (controls).

However, the extracellular matrix (ECM) — a mesh of proteins, sugars, water, and minerals that acts as a scaffold for tissues and cells — has been found to undergo drastic changes in CP, implicating it as the source of excessive stiffness in muscle contractures.

Based on these observations, researchers in the College of Biological Sciences at UC Davis sought to investigate whether changes in the composition and structure of the extracellular matrix could account for the increased stiffness observed in the muscles of CP patients.

The team also examined the architecture of the extracellular matrix, looking for changes that would explain an increased likelihood of contractures.

Biopsies of contractured muscle were collected from 13 children with CP (mean age 10.4 years) who underwent muscle lengthening, as well as from 13 typically developing children who underwent knee surgery. Muscle lengthening is a surgical procedure done in CP to relieve muscle tightness.

The amount of several key extracellular proteins were quantified, including collagen types I, III, IV, and VI, proteoglycan, biglycan, decorin, hyaluronic acid, and uronic acid.

The researchers focused on collagens because they are the main load-bearing structures within the ECM. Collagen is the major connective-tissue protein and an integral constituent of muscles, tendons, and skin. Some collagen types, like collagen type I, join together in long and extremely stretchable fibrils that organize themselves in bundles, called collagen fibers. These fibers are crucial for allowing tendons to connect muscles with bones and withstand large loads.

Type I and III  are the most common type of collagens, with type I associated with high tissue stiffness and type III with tissue compliance. Other types of collagen link them to each other or to other matrix components, including type IV and type VI.

The team also measured collagen crosslinks: bonds that tie together two or more such molecules, further contributing to the strengthening and stiffening of collagen networks.

The ECM also includes abundant glycoproteins — proteins bound to sugars — including proteoglycans such as decorin and biglycan and other sugars like hyaluronic acid. These serve to hydrate and maintain the matrix’s viscosity and elasticity, while some also interact with collagens.

As expected, muscle fibers from patients with CP were about 50% stiffer than samples from typically developing children.

The amount of total collagen “had dramatically increased” in the muscles of children with CP compared with typically developing children, the researchers found. All collagen types showed 3–5 fold increases, as did collagen crosslinks, total proteoglycans, and uronic acid.

Type I collagen, total collagen, and total proteoglycan were good predictors of stiffness, whereas the amount of biglycan was linked with lower stiffness.

Importantly, the collagen I/III ratio was the critical predictor of muscle stiffness in children with cerebral palsy.

“These data emphasize that ECM components, including fibrillar collagens, are critical in determining stiffness and highlight potential negative regulators (biglycan) that may play a therapeutic role in increasing muscle compliance in contractures of patients with cerebral palsy and potentially other fibrotic muscle disorders,” the researchers said.

These results suggest “…a novel adaptation of muscle extracellular matrix in children with cerebral palsy that includes alterations in extracellular matrix protein composition and structure related to mechanical function,” the researchers concluded.

Source Cerebral Palsy News Today

  References
Contribution of extracellular matrix components to the stiffness of skeletal muscle contractures in patients with cerebral palsy, Smith LR, Pichika R, Meza RC, Gillies AR, Baliki MN, Chambers HG, Lieber RL. Connect Tissue Res. 2019 Nov 28:1-12. doi: 10.1080/03008207.2019.1694011. [Epub ahead of print]
  Further reading
Fibre and extracellular matrix contributions to passive forces in human skeletal muscles: An experimental based constitutive law for numerical modelling of the passive element in the classical Hill-type three element model, Marcucci L, Bondì M, Randazzo G, Reggiani C, Natali AN, Pavan PG. PLoS One. 2019 Nov 5;14(11):e0224232. doi: 10.1371/journal.pone.0224232. eCollection 2019. Full text

Muscle contracture and passive mechanics in cerebral palsy, Lieber RL, Fridén J. J Appl Physiol (1985). 2019 May 1;126(5):1492-1501. doi: 10.1152/japplphysiol.00278.2018. Epub 2018 Dec 20.

From single muscle fiber to whole muscle mechanics: a finite element model of a muscle bundle with fast and slow fibers, Marcucci L, Reggiani C, Natali AN, Pavan PG. Biomech Model Mechanobiol. 2017 Dec;16(6):1833-1843. doi: 10.1007/s10237-017-0922-6. Epub 2017 Jun 5.

Pathophysiology of muscle contractures in cerebral palsy, Mathewson MA, Lieber RL. Phys Med Rehabil Clin N Am. 2015 Feb;26(1):57-67. doi: 10.1016/j.pmr.2014.09.005. Review. Full text

Stiff muscle fibers in calf muscles of patients with cerebral palsy lead to high passive muscle stiffness, Mathewson MA, Chambers HG, Girard PJ, Tenenhaus M, Schwartz AK, Lieber RL. J Orthop Res. 2014 Dec;32(12):1667-74. doi: 10.1002/jor.22719. Epub 2014 Aug 19. Full text

Hamstring contractures in children with spastic cerebral palsy result from a stiffer extracellular matrix and increased in vivo sarcomere length, Smith LR, Lee KS, Ward SR, Chambers HG, Lieber RL. J Physiol. 2011 May 15;589(Pt 10):2625-39. doi: 10.1113/jphysiol.2010.203364. Epub 2011 Mar 21. Full text

The extracellular matrix at a glance, Frantz C, Stewart KM, Weaver VM. J Cell Sci. 2010 Dec 15;123(Pt 24):4195-200. doi: 10.1242/jcs.023820. Review. No abstract available. Full text

Skeletal muscle mechanics: implications for rehabilitation, Lieber RL, Bodine-Fowler SC. Phys Ther. 1993 Dec;73(12):844-56. Review.

Ana Pena PhD
Ana is a molecular biologist with a passion for discovery and communication. As a science writer she looks for connecting the public, in particular patient and healthcare communities, with clear and quality information about the latest medical advances. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in genetics, molecular biology, and infectious diseases.
Fact checked by Ana de Barros PhD
Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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