Resveratrol improves motor function in patients with muscular dystrophies: an open-label, single-arm, phase IIa study

Abstract

Muscular dystrophies (MDs) are inherited disorders characterized by progressive muscle weakness. Previously, we have shown that resveratrol (3,5,4′-trihydroxy-trans-stilbene), an antioxidant and an activator of the protein deacetylase SIRT1, decreases muscular and cardiac oxidative damage and improves pathophysiological conditions in animal MD models. To determine whether resveratrol provides therapeutic benefits to patients with MDs, an open-label, single-arm, phase IIa trial of resveratrol was conducted in 11 patients with Duchenne, Becker or Fukuyama MD. The daily dose of resveratrol was 500 mg/day, which was increased every 8 weeks to 1000 and then 1500 mg/day. Primary outcomes were motor function, evaluated by a motor function measure (MFM) scale, muscular strength, monitored with quantitative muscle testing (QMT), and serum creatine kinase (CK) levels. Adverse effects and tolerability were evaluated as secondary outcomes. Despite the advanced medical conditions of the patients, the mean MFM scores increased significantly from 34.6 to 38.4 after 24 weeks of medication. A twofold increase was found in the mean QMT scores of scapula elevation and shoulder abduction. Mean CK levels decreased considerably by 34%. Diarrhoea and abdominal pain was noted in six and three patients, respectively. Resveratrol may provide some benefit to MD patients.

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

“…Overall resveratrol has shown potential to reduce pathology in the mdx mouse model of DMD and highlights the need for this to be tested clinically. A recent 2020 study tested resveratrol supplementation in an open-label, single-arm, phase IIa trial in 11 patients with Duchenne, Becker or Fukuyama muscular dystrophies [ 35 ]. Whilst this study was quite small, they were able to show a significant reduction in creatine kinase levels and improved motor function measurements [ 35 ].…”

“…A recent 2020 study tested resveratrol supplementation in an open-label, single-arm, phase IIa trial in 11 patients with Duchenne, Becker or Fukuyama muscular dystrophies [ 35 ]. Whilst this study was quite small, they were able to show a significant reduction in creatine kinase levels and improved motor function measurements [ 35 ]. These results are highly encouraging and open the door for trials with increased patient numbers.…”

Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy

“…New treatment approaches to ameliorate the dystrophic phenotype include (i) pharmacological interventions using drugs that modulate the immune response and inflammation, abnormal ion homeostasis, impaired excitation-contraction coupling, cellular growth patterns, abnormal metabolic pathways, cholesterol metabolism, oxidative stress and cardio-respiratory complications [8,132,155,209,214];…”

“…New treatment approaches to ameliorate the dystrophic phenotype include (i) pharmacological interventions using drugs that modulate the immune response and inflammation, abnormal ion homeostasis, impaired excitation–contraction coupling, cellular growth patterns, abnormal metabolic pathways, cholesterol metabolism, oxidative stress and cardio-respiratory complications [ 8 , 132 , 155 , 209 , 214 ]; (ii) myoblast transfer therapy [ 15 , 225 , 304 ]; (iii) stem cell therapy [ 24 , 40 , 325 ]; (iv) somatic genome editing using CRISPR/Cas9-mediated exon excision [ 12 , 171 , 218 ]; (v) heat shock protein induction to enhance the natural cellular stress response provided by molecular chaperones [ 108 , 334 ]; (vi) stop codon read-through therapy [ 127 , 264 , 326 ]; (vii) vector transfer therapy [ 121 , 242 , 296 ]; (viii) exon-skipping therapy [ 49 , 131 , 180 ]; (ix) electrical nerve stimulation to induce muscle transitions [ 122 ]; and (x) utrophin substitution therapy [ 193 , 312 , 362 ]. An interesting approach is the repurposing of established pharmacological substances and testing of multi-drug combinations in experimental trials using genetic animal models of Duchenne muscular dystrophy [ 383 ].…”

Regulation of Cytochrome c Oxidase by Natural Compounds Resveratrol, (–)-Epicatechin, and Betaine

“…Due to the nature of its structure, RSV efficiently scavenges ROS and suppresses lipid peroxidation, and in addition, it exerts the anti-oxidative action indirectly by increasing expression of ROS scavenging enzymes [15]. There have been a number of studies showing that RSV enhances muscle performance [42][43][44][45] and alleviates or even prevents cardiovascular disease, neurodegenerative disease, cancer, and metabolic defects [46][47][48][49]. The compound is generally considered non-toxic, excluding mild adverse effects such as nausea, stomach pain, bloating, and diarrhea at high dosages (>1000 mg/day) [50].…”