Increased collagen cross-linking is a signature of dystrophin-deficient muscle

Muscle Nerve. 2016 Jun;54(1):71-8. doi: 10.1002/mus.24998. Epub 2016 Feb 22.


Introduction: Collagen cross-linking is a key parameter in extracellular matrix (ECM) maturation, turnover, and stiffness. We examined aspects of collagen cross-linking in dystrophin-deficient murine, canine, and human skeletal muscle.

Methods: DMD patient biopsies and samples from mdx mice and golden retriever muscular dystrophy dog samples (with appropriate controls) were analyzed. Collagen cross-linking was evaluated using solubility and hydroxyproline assays. Expression of the cross-linking enzyme lysyl oxidase (LOX) was determined by real-time polymerase chain reaction, immunoblotting, and immunofluorescence.

Results: LOX protein levels are increased in dystrophic muscle from all species evaluated. Dystrophic mice and dogs had significantly higher cross-linked collagen than controls, especially in the diaphragm. Distribution of intramuscular LOX was heterogeneous in all samples, but it increased in frequency and intensity in dystrophic muscle.

Conclusion: These findings implicate elevated collagen cross-linking as an important component of the disrupted ECM in dystrophic muscles, and heightened cross-linking is evident in mouse, dog, and man. Muscle Nerve 54: 71-78, 2016.

Keywords: collagen cross-linking; extracellular matrix; fibrosis; lysyl oxidase; muscular dystrophy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Animals
  • Child
  • Collagen / metabolism
  • Diaphragm / metabolism*
  • Dogs
  • Female
  • Humans
  • Hydroxyproline / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Muscle, Skeletal / metabolism*
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / metabolism*
  • Muscular Dystrophy, Duchenne / pathology*
  • Protein-Lysine 6-Oxidase / genetics
  • Protein-Lysine 6-Oxidase / metabolism*
  • RNA, Messenger / metabolism
  • Vimentin / metabolism


  • RNA, Messenger
  • Vimentin
  • Collagen
  • Protein-Lysine 6-Oxidase
  • Hydroxyproline