O1003: Identification of Novel Protein Biomarkers Correlating with Both Cardiac and Skeletal Muscle Indices in Duchenne Muscular Dystrophy

Background: Duchenne muscular dystrophy (DMD) is an X-linked, progressive neuromuscular disorder characterized by cardiac and skeletal myopathy. The cardiac and skeletal muscle manifestations have different ages of onset and rates of progression, suggesting variability in the pathophysiology of dystrophin loss within the respective muscle groups. Pairing proteomics with comprehensive clinical phenotyping allows for the assessment of proteins that overlap with, or are unique to, cardiac and skeletal muscle progression. We aimed to identify novel biomarkers that correlate with cardiac and skeletal disease progression in boys with DMD.

Methods: Sixty subjects with DMD were enrolled; 56 underwent cardiac magnetic resonance (CMR) to determine left ventricular ejection fraction (LVEF), late gadolinium enhancement (LGE), and myocardial circumferential strain (ECC). Of the 60 patients enrolled, 51 underwent quantitative muscle testing, and 33 underwent actigraphy. Aptamer-based technology (SomaScan, SomaLogic, Boulder, CO) evaluated 1300 proteins in plasma sampled at the time of CMR. The significance of correlations between serum protein levels and cardiac or skeletal muscle (MSK) indices were tested using Benjamini-Hochberg corrected p-values (q-values).

Results: The mean age of DMD subjects was 15.5 years old +/- 4.30. Twenty-six subjects had left ventricular dysfunction, defined as LVEF < 55%; 45 subjects had LGE. Forty-five patients were non-ambulatory. Of 1300 proteins analyzed, 208 demonstrated a significant correlation for cardiac but not MSK indices, while 14 showed significant correlation for MSK but not cardiac indices. 10 proteins correlated strongly (q-values < 0.05) with both Cardiac (all LVEF) and MSK indices (Table 1). Protein functions included protein metabolism, extra-cellular matrix regulation, fibrosis, inflammation, and proteins playing a role in glycolysis and bicarbonate transport.

Conclusion: We detected proteins that correlate with both cardiac and skeletal muscle progression; these proteins provide a better understanding of the underlying pathophysiology of DMD in the respective muscle groups. This will provide clues to therapeutic options that could improve either cardiac and/or skeletal myopathy in patients with DMD.