6) Neuromuscular Disorders Volume 25, Supplement 2S314-S315October 2015

Epicatechin enhances mitochondrial biogenesis, increases dystrophin and utrophin, increases follistatin while decreasing myostatin, and improves skeletal muscle exercise response in adults with Becker muscular dystrophy (BMD)

  1. McDonald*,1∙ E. Henricson1 ∙ B. Oskarsson2∙ … ∙ Y. Hathout5 ∙ S. Dugar6 ∙ G. Schreiner6

Abstract

Epicatechin is a structural homologue of a family of PGC1-alpha activating steroid hormones that promote mitochondrial biogenesis and induce skeletal muscle regeneration. Epicatechin stimulates mitochondrial biogenesis and improves muscle structure and function in the mdx and d-sarcoglycan null models. We conducted an open-label pilot study of epicatechin in ambulatory adults with Becker Muscular Dystrophy (BMD). 7 participants received epicatechin 50 mg b.i.d./8 weeks. Pre- and post-assessments included: biceps biopsy Western blot and EM, blood biomarkers, metabolic gas exchange/graded exercise testing, tissue saturation index (TSI) by near-infrared spectroscopy, and muscle strength. Muscle western blot showed significantly increased dystrophin, utrophin and dysferlin levels. We observed increased muscle follistatin (p = 0.002) and decreased myostatin (p = 0.008). Increased markers of muscle regeneration included myogenin, Myf5, MyoD, myosin and SkM actin alpha 1 (all p < 0.033). Increased proteins associated with mitochondrial growth included PGC1-alpha (p = 0.01), AMPK (p = 0.004) and mitofilin (p = 0.007). Plasma Western blot showed increased follistatin (p = 0.0006), decreased myostatin (p = 0.04) and increased follistatin:myostatin ratio (p = 0.0004). Muscle EM showed increased mitochondrial volume and cristae abundance (p = 0.02). Exercise testing showed decreased VO2/kg (p < 0.0001), lactate (p < 0.0001) and heart rate (p < 0.00001) at defined workloads. TSI improved in resting (p < 0.008) and post-exercise states (p < 0.001). Epicatechin induces mitochondrial biogenesis and muscle regeneration in BMD. It is the only oral compound ever demonstrated to both increase plasma follistatin and decrease plasma myostatin, whose ratio may comprise a future pharmacodynamic biomarker. Increased levels of dystrophin and utrophin suggest that stimulation of bioenergetics and muscle regeneration may be a novel therapeutic strategy for dystrophinopathies.