Antioxidant therapy for muscular dystrophy: caveat lector!

O’Halloran, Ken D.; Murphy, Kevin P.; Burns, David P.

doi:10.1113/jp275598

Cited by 4 publications

(4 citation statements)

References 15 publications

(33 reference statements)

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“…Brown and white adipose tissues were decreased in mdx compared with wild type; NAC supplementation resulted in a modest increase in brown adipose tissue mass. Collectively, these are interesting findings in the context of previous research addressing potential side effects of NAC particularly in respect of reductions in body mass [27,75,83]. Left ventricle mass was unaffected by NAC supplementation in mdx mice, while right ventricle mass was decreased.…”

Section: Discussionsupporting

confidence: 53%

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N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

et al. 2019

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Respiratory muscle weakness occurs due to dystrophin deficiency in Duchenne muscular dystrophy (DMD). The mdx mouse model of DMD shows evidence of impaired respiratory muscle performance with attendant inflammation and oxidative stress. We examined the effects of N-acetylcysteine (NAC) supplementation on respiratory system performance in mdx mice. Eight-week-old male wild type (n = 10) and mdx (n = 20) mice were studied; a subset of mdx (n = 10) received 1% NAC in the drinking water for 14 days. We assessed breathing, diaphragm, and external intercostal electromyogram (EMG) activities and inspiratory pressure during ventilatory and non-ventilatory behaviours. Diaphragm muscle structure and function, cytokine concentrations, glutathione status, and mRNA expression were determined. Diaphragm force-generating capacity was impaired in mdx compared with wild type. Diaphragm muscle remodelling was observed in mdx, characterized by increased muscle fibrosis, immune cell infiltration, and central myonucleation. NAC supplementation rescued mdx diaphragm function. Collagen content and immune cell infiltration were decreased in mdx + NAC compared with mdx diaphragms. The cytokines IL-1β, IL-6 and KC/GRO were increased in mdx plasma and diaphragm compared with wild type; NAC decreased systemic IL-1β and KC/GRO concentrations in mdx mice. We reveal that NAC treatment improved mdx diaphragm force-generating capacity associated with beneficial anti-inflammatory and anti-fibrotic effects. These data support the potential use of NAC as an adjunctive therapy in human dystrophinopathies.

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Section: Discussionsupporting

confidence: 53%

“…Furthermore, NAC reduced myosin protein thiol oxidation in mdx limb muscle [27]. Interestingly, NAC has been shown to prevent myofibre damage in mdx mice following exercise [29,75]. Anti-fibrotic actions of NAC have also been observed in animal models of disease.…”

Section: Discussionmentioning

confidence: 99%

N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

et al. 2019

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“…Similar results were observed by treating mdx mice with another antioxidant, (−)-epigallocatechin gallate, the major polyphenolic component of green tea extract, [52]; this molecule has also been used in a recently completed DMD clinical trial (NCT01183767), for which no results have yet been published. However, the use of non-selective antioxidants is quite controversial, as recently discussed [64,65,66].…”

Section: N-acetylcysteine and Antioxidantsmentioning

confidence: 99%

Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy

Vitiello

Tibaudo

Pegoraro

et al. 2019

IJMS

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Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or cell therapy. Cell- and genetic-based therapeutics for DMD have been explored since the 1990s; recently, two of the latter have been approved for clinical use, but their efficacy is still very low. In parallel, there have been great ongoing efforts aimed at targeting the downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, with synthetic or biological molecules. However, as it is always the case with rare diseases, R&D costs for new drugs can represent a major hurdle for researchers and patients alike. This problem can be greatly alleviated by experimenting the use of molecules that had originally been developed for different conditions, a process known as drug repurposing or drug repositioning. In this review, we will describe the state of the art of such an approach for DMD, both in the context of clinical trials and pre-clinical studies.

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“…In particular ( Pinniger et al, 2017 ) using 2% NAC in drinking water for 6 weeks concluded that the reduction of body weight gain in mdx mice was a red flag for considering the use of NAC as a treatment for boys with DMD. Commenting on Pinniger et al, 2017 study ( O'Halloran et al, 2018 ), suggested that some of the reduced weight gain may be attributed to a decrease in body fat and not because of a reduction in lean mass and also that the acidification of the drinking water resulting from the addition of NAC may reduce fluid intake, accounting for some of the weight loss. To address this latter concern, we measured the fluid intake in NAC treated animals compared with no NAC and found no significant effect of NAC on fluid consumption.…”

Section: Discussionmentioning

confidence: 99%

Six weeks of N-acetylcysteine antioxidant in drinking water decreases pathological fiber branching in MDX mouse dystrophic fast-twitch skeletal muscle

et al. 2023

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Introduction: It has been proposed that an increased susceptivity to oxidative stress caused by the absence of the protein dystrophin from the inner surface of the sarcolemma is a trigger of skeletal muscle necrosis in the destructive dystrophin deficient muscular dystrophies. Here we use the mdx mouse model of human Duchenne Muscular Dystrophy to test the hypothesis that adding the antioxidant NAC at 2% to drinking water for six weeks will treat the inflammatory phase of the dystrophic process and reduce pathological muscle fiber branching and splitting resulting in a reduction of mass in mdx fast-twitch EDL muscles.Methods: Animal weight and water intake was recorded during the six weeks when 2% NAC was added to the drinking water. Post NAC treatment animals were euthanised and the EDL muscles dissected out and placed in an organ bath where the muscle was attached to a force transducer to measure contractile properties and susceptibility to force loss from eccentric contractions. After the contractile measurements had been made the EDL muscle was blotted and weighed. In order to assess the degree of pathological fiber branching mdx EDL muscles were treated with collagenase to release single fibers. For counting and morphological analysis single EDL mdx skeletal muscle fibers were viewed under high magnification on an inverted microscope.Results: During the six-week treatment phase NAC reduced body weight gain in three- to nine-week-old mdx and littermate control mice without effecting fluid intake. NAC treatment also significantly reduced the mdx EDL muscle mass and abnormal fiber branching and splitting.Discussion: We propose chronic NAC treatment reduces the inflammatory response and degenerative cycles in the mdx dystrophic EDL muscles resulting in a reduction in the number of complexed branched fibers reported to be responsible for the dystrophic EDL muscle hypertrophy.

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Antioxidant therapy for muscular dystrophy: caveat lector!

Cited by 4 publications

References 15 publications

N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy

Six weeks of N-acetylcysteine antioxidant in drinking water decreases pathological fiber branching in MDX mouse dystrophic fast-twitch skeletal muscle

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