Xanthine oxidase is hyper-active in Duchenne muscular dystrophy

Area of Science:

• Biochemistry
• Molecular Biology
• Physiology

Background:

• Duchenne muscular dystrophy (DMD) involves ischemia and aberrant calcium homeostasis.
• Xanthine oxidase (XO) generates superoxide, potentially exacerbating DMD pathology.
• Elevated XO activity is hypothesized to contribute to DMD pathogenesis.

Purpose of the Study:

• To test if xanthine oxidase activity is elevated in DMD.
• To investigate the role of XO in DMD-related muscle dysfunction.
• To evaluate urinary isoxanthopterin as a noninvasive biomarker for DMD.

Main Methods:

• Measured urinary isoxanthopterin/creatinine in DMD patients and mouse models.
• Assessed skeletal muscle XO protein and mRNA levels in mdx mice.
• Evaluated the effect of XO inhibitors (allopurinol, oxypurinol) on muscle function.
• Measured urinary ortho-tyrosine to confirm oxidative stress.

Main Results:

• Urinary isoxanthopterin/creatinine was elevated in DMD patients and dystrophin-deficient mice (mdx, Scgb-/-).
• XO enzymatic activity was increased in mdx skeletal muscle, despite lower protein levels.
• XO inhibition attenuated exercise-induced increases in urinary isoxanthopterin and protected against eccentric contraction-induced force drop.
• Elevated urinary ortho-tyrosine confirmed oxidative stress in dystrophin-deficient models.

Conclusions:

• Xanthine oxidase is hyper-active in Duchenne muscular dystrophy.
• XO activity contributes to eccentric contraction-induced force drop in dystrophin-deficient muscle.
• Urinary isoxanthopterin shows potential as a noninvasive biomarker for DMD.