Female carriers of BMD and DMD mutations show elevated muscle injury proteins, and muscle loss progression is predicted by plasma ART3 concentration

Topic:

Translational Research

Poster Number: 167 M

Author(s):

Luuli Tran, PhD, Edgewise Therapeutics, Ben Barthel, PhD, Edgewise Therapeutics, Zhe Lyu, Copenhagen Neuromuscular Centre, Rigshospitalet, University of Copenhagen, Nanna Scharff Poulsen, Copenhagen Neuromuscular Centre, Rigshospitalet, University of Copenhagen, Maria Buhl Hjortrup, Copenhagen Neuromuscular Centre, Rigshospitalet, University of Copenhagen, Mads Godtfeldt Stemmerik, Copenhagen Neuromuscular Centre, Rigshospitalet, University of Copenhagen, Tuva Åsatun Solheim, Copenhagen Neuromuscular Centre, Rigshospitalet, University of Copenhagen, Niels Grove Vejlstrup, Department of Cardiology, The Heart Center, Rigshospitalet, Alan Russell, PhD, Edgewise Therapeutics, John Vissing, MD, Neurology at the University of Copenhagen

Duchenne (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive disorders resulting from genetic variants in the dystrophin gene and are characterized by progressive muscle degeneration and functional loss. While affected individuals are primarily male, ~5-20% of female carriers exhibit clinical manifestations such as muscle weakness, which may range from mild to severe. We hypothesized that plasma proteomic signatures reflecting muscle injury would differ between carriers and healthy controls and that longitudinal profiling could identify proteins that correlate with or predict functional changes over time.

Baseline plasma samples were collected from 22 DMD carriers, 15 BMD carriers, and 21 healthy volunteers (HV), and plasma proteomics were analyzed using the SOMAscan 7K platform. Longitudinal samples (mean 6.5 yr follow-up) were obtained from 12 DMD and 8 BMD carriers. Thigh muscle fat fraction (TMFF; DMD n=31; BMD n=22) was measured by muscle MRI, and muscle strength was assessed using Medical Research Council (MRC) scores (DMD n=15; BMD n=8).

At baseline, a previously defined skeletal muscle injury signature was significantly elevated in BMD (p=0.033) and DMD (p<0.001) carriers relative to HV and was higher in DMD than in BMD carriers (p<0.001). Elevated injury signature was associated with greater TMFF (p=0.051) and with a greater likelihood of reduced MRC scores. Gene ontology analysis of high TMFF carriers revealed enrichment of lipid storage and inflammatory pathways and down-regulation of neural pathways. Ecto-ADP-ribosyltransferase (ART3) was lower at baseline in carriers relative to HV and was inversely correlated to TMFF, particularly in DMD carriers. Moreover, low baseline ART3 correlated with more TMFF change at follow-up. These results demonstrate that BMD and DMD carriers show proteomic evidence of muscle injury, which is associated with elevated muscle fat, reduced strength, and reduced ART3, which may serve as a predictive biomarker for progressive fat replacement and loss of muscle strength.