Serum protein biomarkers associated with muscle replacement by fat in DMD

Topic:

Translational Research

Poster Number: 263 T

Author(s):

Alison Barnard, DPT, PhD, University of Florida, Simon Eng, PhD, BioSymetrics, Kevin Ha, PhD, BioSymetrics, Robert Mueller, PhD, University of Florida, William Triplett, BS, University of Florida, Rebecca Willcocks, PhD, University of Florida, Sean Forbes, PhD, RESEARCH, William D Rooney, PhD, Oregan Health and Science University, Pietro Spitali, PhD, Leiden University Medical Center, Krista Vandenborne, PhD, University of Florida, Glenn Walter, PhD, University of Florida

Background: Progressive fatty replacement of skeletal muscle is a hallmark of Duchenne muscular dystrophy (DMD) and reflects disease progression. Magnetic resonance (MR)-derived fat fraction is a robust, noninvasive biomarker of this process; however, corresponding circulating biomarkers have not been defined. The objective of this study was to identify serum protein biomarkers associated with MR-derived muscle fat fraction in DMD.
Methods: In total, 295 serum samples from 80 individuals with DMD enrolled in the ImagingDMD natural history study underwent proteomic profiling using the 7K SomaScan assay. Mean age at first sample collection was 10.9 years, and participants contributed multiple longitudinal samples. Linear mixed-effects models were used to evaluate associations between serum protein expression and MR spectroscopy-derived fat fraction of the soleus and vastus lateralis muscles, adjusting for age and corticosteroid use, with false discovery rate correction.
Results: One hundred twenty-six protein probes were significantly associated with soleus fat fraction (71 negative; 55 positive), and 345 probes were associated with vastus lateralis fat fraction (311 negative, 34 positive). Seventy-four probes were shared between muscles, including 61 negative and 13 positive associations. Negatively associated proteins were enriched for markers of muscle connective tissue integrity (e.g. cartilage oligomeric matrix protein and osteomodulin), myogenesis (e.g. delta-like 1 homolog and repulsive guidance molecule A/B), and anti-adipogenic pathways (Wnt and hedgehog signaling proteins). In contrast, positively associated proteins included adipokines (leptin and fatty acid binding protein 4) and fibrosis/extracellular matrix proteins (serum amyloid p component and tissue inhibitor of metalloproteinases 4), consistent with progressive fibrofatty muscle replacement.
Conclusion: Distinct serum proteomic profiles are associated with muscle fat fraction in DMD, reflecting biological pathways related to muscle preservation, adipogenesis, and fibrotic remodeling. These findings demonstrate the potential utility of circulating proteins as minimally invasive biomarkers of disease progression and provide insight into mechanisms underlying muscle degeneration.