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Published on: May 24, 2016
Nutraceutical and pharmaceutical cocktails did not preserve diaphragm muscle function or reduce muscle damage in
H R Spaulding1, T Quindry2, J C Quindry2
1Department of Animal Science, Iowa State University, Ames, IA, USA.
New Findings:
What is the central question of this study? We previously demonstrated that quercetin transiently preserved respiratory function in dystrophin-deficient mice. To gain lasting therapeutic benefits, we tested quercetin in combination with nicotinamide riboside, lisinopril and prednisolone in the D2-mdx model. What is the main finding and its importance? We demonstrated that these quercetin-based cocktails did not preserve respiratory or diaphragmatic function or reduce histological damage after 7 months of treatment starting at 4 months of age.
Abstract:
Duchenne muscular dystrophy is characterized by the absence of dystrophin protein and causes muscle weakness and muscle injury, culminating in respiratory failure and cardiomyopathy. Quercetin transiently improved respiratory function but failed to maintain long-term therapeutic benefits in mdx mice. In this study, we combined quercetin with nicotinamide riboside (NR), lisinopril and prednisolone to assess the efficacy of quercetin-based cocktails. We hypothesized that quercetin, NR and lisinopril independently would improve respiratory function and decrease diaphragmatic injury and when combined would have additive effects. To address this hypothesis, in vivo respiratory function, in vitro diaphragmatic function and histological injury were assessed in DBA (healthy), D2-mdx (dystrophic) and D2-mdx mice treated with combinations of quercetin, NR and lisinopril from 4 to 11 months of age. Respiratory function, assessed using whole-body plethysmography, was largely similar between healthy and dystrophin-deficient mice. Diaphragm specific tension was decreased by ∼50% in dystrophic mice compared with healthy mice (P < 0.05), but fatigue resistance was similar between groups. Contractile area was decreased by ∼10% (P < 0.05) and fibrotic area increased from 3.5% in healthy diaphragms to 27% (P < 0.05) in dystrophic diaphragms. Contrary to expectations, these functional and histological parameters of disease were not offset by any intervention. These data suggest that quercetin, NR and lisinopril, independently and in combination, did not prevent diaphragmatic injury or preserve respiratory function.
Insights
Quercetin-based cocktails, including nicotinamide riboside and lisinopril, failed to preserve respiratory or diaphragmatic function in a mouse model of Duchenne muscular dystrophy over seven months. These findings indicate a lack of long-term therapeutic benefit for these specific interventions.
Area of Science:
- Biomedical research
- Musculoskeletal disorders
- Respiratory medicine
Background:
- Duchenne muscular dystrophy (DMD) involves dystrophin absence, leading to muscle weakness, respiratory failure, and cardiomyopathy.
- Quercetin showed transient benefits in respiratory function in dystrophin-deficient mice but lacked sustained efficacy.
- Developing effective long-term therapies for DMD remains a critical challenge.
Purpose of the Study:
- To evaluate the long-term efficacy of quercetin-based combination therapies for Duchenne muscular dystrophy.
- To assess the impact of quercetin combined with nicotinamide riboside (NR), lisinopril, and prednisolone on respiratory and diaphragmatic function.
- To determine if these interventions could mitigate histological damage in a D2-mdx mouse model.
Main Methods:
- D2-mdx mice and healthy DBA controls were treated from 4 to 11 months of age with quercetin, NR, lisinopril, and their combinations.
- In vivo respiratory function was assessed using whole-body plethysmography.
- In vitro diaphragmatic function (specific tension, fatigue resistance) and histological injury (fibrotic area) were evaluated.
Main Results:
- No significant preservation of respiratory function was observed in treated dystrophic mice compared to controls.
- Diaphragmatic specific tension decreased by approximately 50% and contractile area by 10% in dystrophic mice.
- Histological analysis revealed a significant increase in fibrotic area (3.5% to 27%) in dystrophic diaphragms, which was not improved by any intervention.
- Contrary to expectations, none of the tested interventions, individually or in combination, offset disease-related functional or histological parameters.
Conclusions:
- Quercetin, nicotinamide riboside, and lisinopril, whether used independently or in combination, did not prevent diaphragmatic injury or preserve respiratory function in the D2-mdx mouse model over a 7-month treatment period.
- These findings suggest that the tested quercetin-based cocktails do not offer lasting therapeutic benefits for the respiratory and diaphragmatic complications of DMD.
- Further research is needed to identify effective long-term therapeutic strategies for Duchenne muscular dystrophy.
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