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Published on: September 14, 2019
ARC-18 Improved Motor Performance Through Inhibiting ACLY-Mediated Smad2/3 Acetylation in a Model of Duchenne
Chongyang Chen1,2,3, Bingge Zhang1,3, Chao Yang4
1Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Background:
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle weakness, with inflammation and fibrosis contributing to its pathogenesis. Despite advancements in genetic disease-modifying treatment, there is currently no effective pharmacological treatment for DMD.
Methods:
New compound ARC-18, a derivative of Arctigenin known for its anti-inflammatory activity, was designed and synthesized in our lab and administered prophylactically to 2-month-old mdx mice for 60 days. The motor performance was investigated by rotarod test, climbing-pole test, grip strength test, hanging endurance test, treadmill endurance test and gait analysis. Afterwards, molecular biological experiments, including proteomics, immunohistochemistry, immunofluorescence, western blots, gene transfection and immunoprecipitation, were employed to investigate the molecular mechanism of ARC-18 in the treatment of mdx.
Results:
ARC-18 significantly ameliorated the motor performance of DMD mice (rotating time +65.9%, p < 0.01; hanging time +59.7%, p < 0.05; grip strength +32.1%, p < 0.0001; climbing time -29.0%, p < 0.0001; numbers of electric shocks -69.3%, p < 0.01) by up-regulating the expression of dystrophin-associated proteins (dystrophin, p < 0.01; α-dystroglycan, p < 0.01) and down-regulating the expression of muscle satellite/stem cell proteins (Pax7, p < 0.05; Myod, p < 0.05; Myog, p < 0.05; α-SMA, p < 0.01; fibronectin, p < 0.001; collagen I, p < 0.05). ARC-18 prevented the progression of muscle fibrosis, reduced inflammatory factors transforming growth factor (TGF) β1 (p < 0.05), IL-1β (p < 0.05) and TNF-α (p < 0.05) levels, and promoted the structural integrity of gastrocnemius and triceps muscles. Proteomics analysis demonstrated that ARC-18 treatment reversed the protein expression pattern of DMD model mice, with ATP-citrate synthase (ACLY) enriched in the TCA cycle pathway, showing a significant correlation with DMD expression levels (R = -0.72, p = 0.00031). Further investigations revealed that ARC-18 directly bound with ACLY (EC50 = 120.2 nM) to promote its degradation by the proteasome system and suppressed the ACLY-mediated acetylation of Smad2/3 (p < 0.01) to reduce its nuclear localization (p < 0.05) to inhibit fibrosis.
Conclusions:
Our study indicated that oral ARC-18 treatment decelerated the progression of neuromuscular disease in a reliable DMD animal model, suggesting its potential as a promising drug for DMD.
Insights
New compound ARC-18 effectively treats Duchenne muscular dystrophy (DMD) in mice by improving motor function and reducing muscle fibrosis. This promising drug candidate decelerates neuromuscular disease progression in a reliable DMD animal model.
Area of Science:
- Biochemistry
- Pharmacology
- Genetics
Background:
- Duchenne muscular dystrophy (DMD) is a progressive genetic disorder causing muscle weakness, inflammation, and fibrosis.
- Current treatments for DMD focus on genetic modification, with limited pharmacological options available.
Purpose of the Study:
- To evaluate the efficacy of a novel compound, ARC-18, derived from Arctigenin, in treating Duchenne muscular dystrophy.
- To investigate the molecular mechanisms underlying ARC-18's therapeutic effects in a mouse model of DMD.
Main Methods:
- ARC-18 was administered prophylactically to mdx mice for 60 days.
- Motor performance was assessed using various tests including rotarod, grip strength, and gait analysis.
- Molecular mechanisms were explored through proteomics, western blots, and immunoprecipitation.
Main Results:
- ARC-18 significantly improved motor performance and muscle strength in DMD mice.
- Treatment upregulated dystrophin-associated proteins and downregulated muscle satellite/stem cell markers.
- ARC-18 reduced muscle fibrosis, inflammatory factors (TGF-β1, IL-1β, TNF-α), and inhibited ACLY-mediated Smad2/3 acetylation.
Conclusions:
- ARC-18 treatment decelerated neuromuscular disease progression in a DMD animal model.
- The compound demonstrates potential as a promising pharmacological treatment for Duchenne muscular dystrophy.
