Nutraceutical and Pharmaceutical Interventions Improve Fatigue Resistance in Dystrophic Skeletal Muscle
Authors: Spaulding Hannah Rose , Quindry Tiffany , Quindry John , Selsby Joshua 
Published: June 2021

Progressive muscle injury and weakness are hallmarks of Duchenne muscular dystrophy (DMD), which is caused by the absence of functional dystrophin protein. Likewise, chronic muscle injuries are common in military personnel. We have previously shown PGC‐1α‐mediated protection of dystrophic muscle via gene transfer approaches, however, investigations using quercetin (Q) to activate the PGC‐1α pathway have been equivocal. Quercetin activates PGC‐1α through Sirtuin‐1, an NAD+‐dependent deacetylase, however, NAD+ may be depleted in dystrophic skeletal muscle. Therefore, the purpose of this investigation was to determine the extent to which supplementation with Q and nicotinamide riboside (NR), an NAD+ precursor, alone and in combination, improved function of dystrophic skeletal muscle. We hypothesized that the addition of Q or NR would improve diaphragm, soleus and extensor digitorum longus (EDL) muscle function, and when given in combination would cause synergistic effects. To address this hypothesis, muscle function from DBA (healthy), D2‐mdx (dystrophin deficient), and D2‐mdx mice fed Q (0.2% of diet), NR (400 mg/kg/d), and Q/NR was assessed. In addition, to mimic typical pharmacology of DMD patients an additional group was fed Q/NR and treated with prednisone (10 mg/L; Pred) and lisinopril (66 mg/L: Lis). Treatment was started at 4 mo of age under blinded conditions and ended upon tissue collection at 11 mo of age. Dystrophin deficiency impaired diaphragm specific tension and was not corrected by treatments, nor was fatigue resistance improved. In the EDL, dystrophin deficiency decreased resistance to contraction‐induced injury that was partially restored in the Q/NR/Lis/Pred group compared to untreated D2‐mdx. Specific tension in the EDL and soleus was decreased in dystrophic muscle and was not altered by treatments. Interestingly, Q, NR, and Q/NR increased soleus fatigue resistance through 1 min of a fatigue protocol compared to untreated dystrophic controls, but was similar thereafter (10 min). Fatigue resistance was increased throughout the fatigue protocol in the Q/NR/Lis/Pred group compared to D2‐mdx. This finding suggests that Q, NR or Q/NR may improve soleus glycolytic capacity resulting in sustained force production for the first minute of exercise and that the addition of Lis and Pred augments these effects. In total these data suggest that treatment with Q, NR, and Q/NR provide limited protection to dystrophic muscle that is enhanced by the addition of Lis/Pred. As many activities of daily living are completed within 1 min, increased fatigue resistance demonstrated herein, while modest, may decrease disease burden in DMD patients and in other chronic muscle injury conditions.Support or Funding InformationSupported by Parent Project Muscular Dystrophy, Ryan's Quest and Michael's Cause.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.