Plasma Metabolic Profiling Suggests Enrichment of Glycolytic Pathways over Fatty Acid Oxidation in Becker Muscular Dystrophy


Clinical Trials

Poster Number: 71


Angela Peter, PhD, Edgewise Therapeutics, Andrew Schwab, PhD, Metabolon, Inc., Joanne Donovan, MD, Edgewise Therapeutics, Alan Russell, PhD, Edgewise Therapeutics

Becker muscular dystrophy (BMD) is a serious, progressive muscle myopathy caused by mutations in the dystrophin gene resulting in a truncated protein, which leads to enhanced contraction-induced injury, muscle degeneration and muscle replacement with fat and fibrotic tissue. We sought to understand whether alterations in metabolic signatures were observed in BMD. Plasma samples from 16 healthy volunteers were compared to 7 age-matched BMD patient plasma samples using an analysis platform created by Metabolon Inc (Durham, NC). Each sample was analyzed on both LC/MS/MS and Polar LC platforms. Results were compared to a library of standards for metabolite identification and for metabolite quantitation by peak area integration. Principal Component Analysis (PCA) of all samples showed healthy and BMD individuals clustered with clear separation between groups suggesting a metabolic shift in BMD patients. The metabolic shifts identified in BMD plasma were further supported by statistical summary count tables which revealed 30% of biochemicals within the library were significantly changed in BMD subjects relative to healthy volunteer controls. Within the identified biochemical changes, 88 (21.5%) were upregulated while 322 (78.5%) were downregulated in the BMD cohort compared to healthy controls. Notably, multiple free fatty acids (FFAs) were decreased with many reaching statistical significance in BMD subjects compared to controls. Conversely, glucose and several glycolytic intermediates were either significantly increased or were trending higher in BMD patients. These metabolic shifts in BMD compared to controls, including, changes in FFA, fatty acid oxidation, and carbohydrate metabolism potentially reflect key energetic changes in skeletal muscle and may represent novel disease signature biomarkers for BMD that merit further investigation.