Related Experiment Video
Updated: Jun 4, 2025
CRISPR/Cas9 Technology in Restoring Dystrophin Expression in iPSC-Derived Muscle Progenitors
Published on: September 14, 2019
The Potential of Targeting APE1/Ref-1 as a Therapeutic Intervention for Duchenne Muscular Dystrophy
Hannah Lalunio1,2, Nicole Stupka1,2, Craig A Goodman2,3,4
1Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, Parkville, Australia.
Abstract:
Significance: Inflammation and oxidative stress play crucial roles in the development and progression of skeletal muscle diseases. This review aims to examine the existing evidence regarding the involvement and inhibition of APE1/Ref-1 (apurinic/apyrimidinic endonuclease 1/redox factor 1) in diseases, then extrapolate this evidence to the context of skeletal muscle and discuss the potential beneficial effects of APE1/Ref-1 inhibition in ameliorating myopathy with a particular focus on dystrophic pathology. Critical Issues: Currently, therapeutic interventions targeting pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor erythroid 2-related factor 2 (NRF2), have shown limited efficacy in both clinical and preclinical settings. Thus, there is a need for a more comprehensive treatment approach. Recent Advances: APE1/Ref-1 is a multifunctional protein that was initially identified as being involved in DNA repair. However, newer research has revealed its additional role as a redox-sensitive regulator of transcription factors, including NF-κB and NRF2. Numerous studies have reported increased expression of APE1/Ref-1 in various disorders and have demonstrated the beneficial effects of inhibiting its redox function using the small molecular inhibitor, APX3330. Although these pathways are similarly dysregulated in neuromuscular disorders, the specific role of APE1/Ref-1 in skeletal muscle remains unclear, with only a limited number of studies noting its presence in this tissue. Future Directions: Further studies investigating the role of APE1/Ref-1 in skeletal muscle and identifying whether APE1/Ref-1 is up- or downregulated in dystrophic skeletal muscle would be required to determine whether upregulating or inhibiting the redox function of APE1/Ref-1 will alleviate chronic inflammation and heightened oxidative stress. Antioxid. Redox Signal. 42, 641-654.
Insights
This review explores apurinic/apyrimidinic endonuclease 1/redox factor 1 (APE1/Ref-1) in skeletal muscle diseases. Inhibiting APE1/Ref-1 may offer a new therapeutic strategy for myopathies by reducing inflammation and oxidative stress.
Area of Science:
- Biochemistry
- Molecular Biology
- Cellular Biology
Background:
- Inflammation and oxidative stress are key drivers in skeletal muscle diseases.
- Current therapies targeting NF-κB and NRF2 pathways show limited efficacy.
- APE1/Ref-1, a DNA repair enzyme, also regulates transcription factors like NF-κB and NRF2.
Purpose of the Study:
- To review the role of APE1/Ref-1 in disease.
- To extrapolate APE1/Ref-1's function to skeletal muscle pathology.
- To discuss APE1/Ref-1 inhibition as a potential therapy for myopathies, especially muscular dystrophy.
Main Methods:
- Literature review of existing studies on APE1/Ref-1.
- Analysis of APE1/Ref-1's redox function and its targets (NF-κB, NRF2).
- Extrapolation of findings to skeletal muscle disease models and human pathology.
Main Results:
- APE1/Ref-1 is implicated in various disorders, with its inhibition showing therapeutic benefits.
- APE1/Ref-1's role in skeletal muscle is understudied, with limited data on its expression in myopathies.
- Dysregulation of NF-κB and NRF2 pathways is common in neuromuscular disorders.
Conclusions:
- Further research is needed to clarify APE1/Ref-1's specific role in skeletal muscle.
- Determining if APE1/Ref-1 is up- or downregulated in dystrophic muscle is crucial.
- Targeting APE1/Ref-1's redox function could be a novel therapeutic approach for myopathies.
