Xanthine oxidase is hyper-active in Duchenne muscular dystrophy

Angus Lindsay, Preston M. McCourt, Peter I Karachunski, Dawn A Lowe, James M Ervasti

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Generation of superoxide by xanthine oxidase can be stimulated under ischemic and aberrant calcium homeostasis. Because patients and mice with Duchenne muscular dystrophy (DMD) suffer from ischemia and excessive calcium influx, we tested the hypothesis that xanthine oxidase activity is elevated and contributes to disease pathology. Xanthine oxidase activity was measured by urinary isoxanthopterin in DMD patients at rest and in response to exercise. Urinary isoxanthopterin/creatinine was elevated compared to age-matched controls and Becker muscular dystrophy (BMD) patients. Concentrations were also increased after a six minute walk test in ambulatory patients. We also measured urinary isoxanthopterin in wildtype mice and a number of dystrophic mouse models; the DMD mouse model (mdx), mdx mice overexpressing a variety of transgenic miniaturized and chimeric skeletal muscle-specific dystrophins and utrophin and the β-sarcoglycan deficient (Scgb-/-) mouse which represents type 2E human limb-girdle muscular dystrophy. Mdx and Scgb-/- mice had greater urinary isoxanthopterin/creatinine than wildtype mice while mdx mice expressing dystrophin or utrophin linking the extracellular matrix to the actin cytoskeleton were not different than wildtype. We also measured higher levels of urinary ortho-tyrosine in humans and mice deficient for dystrophin to confirm elevated oxidative stress. Surprisingly, mdx had lower xanthine oxidase protein levels and higher mRNA in gastrocnemius muscle compared to wildtype mice, however, the enzymatic activity of skeletal muscle xanthine oxidase was elevated above wildtype and a transgenic rescued mdx mouse (DysΔMTB-mdx). Downhill treadmill running also caused significant increases in mdx urinary isoxanthopterin that was prevented with the xanthine oxidase inhibitor allopurinol. Similarly, in vitro eccentric contraction-induced force drop of mdx muscle was attenuated by the allopurinol metabolite, oxypurinol. Together, our data suggests hyper-activity of xanthine oxidase in DMD, identifies xanthine oxidase activity as a contributing factor in eccentric contraction-induced force drop of dystrophin-deficient skeletal muscle and highlights the potential of isoxanthopterin as a noninvasive biomarker in DMD.

Original languageEnglish (US)
Pages (from-to)364-371
Number of pages8
JournalFree Radical Biology and Medicine
Volume129
DOIs
StatePublished - Dec 1 2018

Fingerprint

Duchenne Muscular Dystrophy
Xanthine Oxidase
Inbred mdx Mouse
Dystrophin
Muscle
Skeletal Muscle
Utrophin
Allopurinol
Creatinine
Oxypurinol
Sarcoglycans
Calcium
Exercise equipment
Oxidative stress
Biomarkers
Pathology
Metabolites
Actin Cytoskeleton
Superoxides
Running

Keywords

  • Allopurinol
  • Duchenne muscular dystrophy
  • Dystrophin
  • Gene therapy
  • Isoxanthopterin
  • Mdx
  • Oxidative stress
  • Pterin
  • Xanthine oxidase

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Xanthine oxidase is hyper-active in Duchenne muscular dystrophy. / Lindsay, Angus; McCourt, Preston M.; Karachunski, Peter I; Lowe, Dawn A; Ervasti, James M.

In: Free Radical Biology and Medicine, Vol. 129, 01.12.2018, p. 364-371.

Research output: Contribution to journalArticle

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