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Nitric Oxide (NO) and Duchenne Muscular Dystrophy: NO Way to Go?

Cara A Timpani1,2, Kamel Mamchaoui3, Gillian Butler-Browne3

  • 1Institute for Health and Sport, Victoria University, Melbourne 8001, Victoria, Australia.

Antioxidants (Basel, Switzerland)
|December 16, 2020
PubMed

Insights

Nitric oxide (NO) signaling therapies failed in Duchenne Muscular Dystrophy (DMD) clinical trials. Acute nitrite treatment worsened muscle damage in DMD myoblasts, indicating NO replacement therapy needs re-evaluation.

Area of Science:

  • Biomedical Science
  • Muscle Physiology
  • Duchenne Muscular Dystrophy Research

Background:

  • Duchenne Muscular Dystrophy (DMD) presents a significant gap between preclinical findings and clinical outcomes.
  • Phosphodiesterase inhibitors (sildenafil, tadalafil) targeting nitric oxide (NO) signaling showed promise in the mdx mouse model but failed in human clinical trials.
  • Previous attempts at NO modulation via chronic nitrate supplementation in mdx mice exacerbated muscle damage and nitrosative stress.

Purpose of the Study:

  • To investigate the efficacy and safety of NO-related therapies for Duchenne Muscular Dystrophy.
  • To understand the detrimental effects of NO signaling modulation in DMD.
  • To propose alternative strategies for NO replacement therapy in DMD.

Main Methods:

  • Review of clinical trial data for phosphodiesterase inhibitors in DMD.
  • Analysis of chronic nitrate supplementation effects in the mdx mouse model.
  • In vitro assessment of acute nitrite treatment on human DMD myoblasts.

Main Results:

  • Sildenafil and tadalafil failed to improve primary outcomes in DMD clinical trials despite preclinical efficacy.
  • Chronic nitrate supplementation in mdx mice led to increased muscle damage and nitrosative stress.
  • Acute nitrite treatment demonstrated detrimental effects on human DMD myoblasts.

Conclusions:

  • NO signaling modulation strategies, including phosphodiesterase inhibitors and nitrate supplementation, are ineffective and potentially harmful for DMD.
  • Acute nitrite administration is detrimental to DMD myoblasts.
  • Novel approaches are required for developing effective NO replacement therapies for Duchenne Muscular Dystrophy.
Keywords:
Duchenne muscular dystrophymetabolismnitric oxidenitritereactive oxygen speciessuperoxide

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