Long-Term Quercetin Dietary Enrichment Partially Protects Dystrophic Skeletal Muscle

Abstract

Duchenne muscular dystrophy (DMD) results from a genetic lesion in the dystrophin gene and leads to progressive muscle damage. PGC-1α pathway activation improves muscle function and decreases histopathological injury. We hypothesized that mild disease found in the limb muscles of mdx mice may be responsive to quercetin-mediated protection of dystrophic muscle via PGC-1α pathway activation. To test this hypothesis muscle function was measured in the soleus and EDL from 14 month old C57, mdx, and mdx mice treated with quercetin (mdxQ; 0.2% dietary enrichment) for 12 months. Quercetin reversed 50% of disease-related losses in specific tension and partially preserved fatigue resistance in the soleus. Specific tension and resistance to contraction-induced injury in the EDL were not protected by quercetin. Given some functional gain in the soleus it was probed with histological and biochemical approaches, however, in dystrophic muscle histopathological outcomes were not improved by quercetin and suppressed PGC-1α pathway activation was not increased. Similar to results in the diaphragm from these mice, these data suggest that the benefits conferred to dystrophic muscle following 12 months of quercetin enrichment were underwhelming. Spontaneous activity at the end of the treatment period was greater in mdxQ compared to mdx indicating that quercetin fed mice were more active in addition to engaging in more vigorous activity. Hence, modest preservation of muscle function (specific tension) and elevated spontaneous physical activity largely in the absence of tissue damage in mdxQ suggests dietary quercetin may mediate protection.

PGC‐1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle

“…Western blotting was performed as previously described (Spaulding, Ballmann, Quindry, & Selsby, ). Briefly, whole homogenate, nuclear protein fractions, and cytoplasmic protein fractions were extracted from powdered gastrocnemius muscles.…”

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

“…Indeed, vector‐mediated and transgenic overexpression of PGC‐1α in dystrophic muscle reduced muscle damage and preserved muscle function (Chan et al., 2014; Handschin et al., 2007; Hollinger & Selsby, 2015; Hollinger et al., 2013; Selsby, Morine, Pendrak, Barton, & Sweeney, 2012). Given the success of PGC‐1α overexpression, we began to investigate the effect of quercetin, a natural flavonoid that stimulates PGC‐1α activity, on disease severity in dystrophic muscle (Ballmann et al., 2017a,b; Ballmann, Hollinger, Selsby, Amin, & Quindry, 2015; Hollinger et al., 2015; Selsby, Ballmann, Spaulding, Ross, & Quindry, 2016; Spaulding, Ballmann, Quindry, & Selsby, 2016). Quercetin serves to increase PGC‐1α activity through SIRT1, an NAD + ‐dependent deacetylase (Dong et al., 2014; Nemoto, Fergusson, & Finkel, 2005).…”

“…In studies in which quercetin was administered for 6 months, quercetin decreased histological injury in dystrophic diaphragms and hearts (Ballmann et al., 2015; Hollinger et al., 2015); however, after 12 months of treatment, skeletal muscle function and histological damage were similar in quercetin‐treated and untreated muscle (Selsby et al., 2016; Spaulding et al., 2016). We also found that quercetin improved respiratory function for the first 4–6 months of treatment, but by the conclusion of the study (14 months of age) respiratory function was similar between treated and untreated dystrophic mice (Selsby et al., 2016).…”

Quel avenir pour la dystrophine ?

“…L'efficacité des inhibiteurs de l'enzyme de conversion (IEC) sur le déve-loppement de la cardiomyopathie est également bien documentée [54]. D'autres thérapeutiques ou supplémentations diététiques font encore l'objet de recherche [55][56][57][58][59][60][61]. Il semble donc que l'on s'achemine vers des théra-peutiques plurielles qui pourraient être associées, de manière plus ou moins personnalisée, en fonction des données génétiques et cliniques.…”