Nutraceutical and pharmaceutical cocktails did not preserve diaphragm muscle function or reduce muscle damage in D2-mdx mice.

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 diaphragm function nor reduce histological damage following 7 months of treatment starting at 4 months of age. ABSTRACT: Duchenne muscular dystrophy (DMD) 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 diaphragm injury, and when combined would have additive effects. To address this hypothesis, in vivo respiratory function, in vitro diaphragm 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 4-11 months of age. Respiratory function was largely similar between healthy and dystrophin-deficient mice using whole body plethysmography. Diaphragm specific tension was decreased by approximately 50% in dystrophic mice compared to healthy mice (p < 0.05), however, fatigue resistance was similar between groups. Contractile area was decreased by approximately 10% (p < 0.05) while fibrotic area was 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 diaphragm injury nor preserve respiratory function. This article is protected by copyright. All rights reserved.