Resveratrol Promotes Hypertrophy in Wildtype Skeletal Muscle and Reduces Muscle Necrosis and Gene Expression of Inflammatory Markers in Mdx Mice

Abstract

Duchenne muscular dystrophy (DMD) is a progressive fatal neuromuscular disorder with no cure. Therapies to restore dystrophin deficiency have been approved in some jurisdictions but long-term effectiveness is yet to be established. There is a need to develop alternative strategies to treat DMD. Resveratrol is a nutraceutical with anti-inflammatory properties. Previous studies have shown high doses (100–400 mg/kg bodyweight/day) benefit mdx mice. We treated 4-week-old mdx and wildtype mice with a lower dose of resveratrol (5 mg/kg bodyweight/day) for 15 weeks. Voluntary exercise was used to test if a lower dosage than previously tested could reduce exercise-induced damage where a greater inflammatory infiltrate is present. We found resveratrol promoted skeletal muscle hypertrophy in wildtype mice. In dystrophic muscle, resveratrol reduced exercise-induced muscle necrosis. Gene expression of immune cell markers, CD86 and CD163 were reduced; however, signalling targets associated with resveratrol’s mechanism of action including Sirt1 and NF-κB were unchanged. In conclusion, a lower dose of resveratrol compared to the dosage used by other studies reduced necrosis and gene expression of inflammatory cell markers in dystrophic muscle suggesting it as a therapeutic candidate for treating DMD.

The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

“…One of these compounds is resveratrol, a natural compound that increases SIRT1 expression which stimulates the SIRT1/PGC-1α axis in mdx mice [ 75 , 76 ]. Several studies have shown the efficacy of resveratrol treatment in ameliorating dystrophic pathology in mdx mice, showing it can improve mitophagy [ 44 , 46 ], reduce ROS levels [ 76 ], reduce inflammation [ 45 , 77 , 78 ], and increase utrophin [ 77 ] expression. One study compared the beneficial effects of resveratrol to the gold standard α-methyl prednisolone.…”

Oxidative Stress, Inflammation and Connexin Hemichannels in Muscular Dystrophies

“…Indeed, administration of 0.4 g resveratrol/kg to mdx mice prevent mitochondria accumulation and reduced ROS levels [ 212 , 213 ]. This polyphenol further promotes skeletal muscle hypertrophy in wild-type mice [ 214 ] and attenuates, either by itself or in combination with exercise training, the skeletal muscle atrophy induced in different disease animal models [ 215 , 216 , 217 , 218 ], including DMD [ 219 ]. In mdx mice, it also reduces skeletal muscle necrosis and the expression of inflammatory markers [ 214 ].…”

“…This polyphenol further promotes skeletal muscle hypertrophy in wild-type mice [ 214 ] and attenuates, either by itself or in combination with exercise training, the skeletal muscle atrophy induced in different disease animal models [ 215 , 216 , 217 , 218 ], including DMD [ 219 ]. In mdx mice, it also reduces skeletal muscle necrosis and the expression of inflammatory markers [ 214 ]. As evaluated in a pilot randomized controlled trial in senior adults, it enhances the aerobic capacity and improves skeletal muscle mitochondrial function in combination with exercise [ 220 ].…”

“…It is noteworthy that most of the studies in mdx mice showing that resveratrol improved the dystrophic pathology used doses ranged from 100–400 mg/Kg/day [ 216 , 217 , 218 , 219 ], which are 7 to 28-fold higher than maximal doses used in human [ 220 , 222 ]. Only a recent study showed that a low dose of resveratrol (5 mg/Kg/day) reduced exercise-induced skeletal muscle necrosis in mdx mice, as measured by inflammatory infiltrate, myofibres with fragmented sarcoplasm and areas of regenerating myofibres [ 214 ]. However, this low dose of resveratrol did not reduce necrosis in the quadriceps of sedentary mdx mice, nor did it increase skeletal muscle hypertrophy, as observed in wild-type mice.…”

Nutraceuticals in Immune Function

“…One such condition is Duchenne muscular dystrophy (DMD), a progressive and fatal neuromuscular disorder with no cure. Woodman et al [ 12 ] treated mdx mice with a low dose of resveratrol (5 mg/kg body weight/day) for 15 weeks. The study found resveratrol to reduce exercise-induced muscle necrosis in dystrophic muscle and lower gene expression of immune cell markers cluster of differentiation (CD) 86 and CD163.…”