SLC34A2 as a Protein Biomarker for Facioscapulohumeral Muscular Dystrophy (FSHD) <i>in-vitro</i> and <i>in-situ</i>

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common dystrophy and affects about 1 in 15,000 people globally. In FSHD patients, epigenetic dysregulation leads to aberrant expression of the transcription factor DUX4 in skeletal muscle. DUX4 is a pioneer transcription factor with many downstream targets, and although the exact mechanism of FSHD muscle pathology is still unknown, it is the area of active research and several promising therapeutics directed towards the expression of DUX4 are in clinical trial. FSHD biomarker characterization remains a high priority to evaluate therapeutic responses. Our laboratory is investigating the protein SLC34A2 as a potential FSHD biomarker. As a downstream target of DUX4, SLC34A2 is not typically expressed in healthy skeletal muscle, but its protein is increased significantly in FSHD muscle and cell lysates, making it a potential readout of FSHD disease progression. SLC34A2 encodes a sodium-phosphate co-transporter expressed in lung, kidney, and gut epithelium, but not in mature muscle. Previously, we showed that SLC34A2 antibodies co-stain FSHD muscle biopsies, FSHD cultured myotubes, and our model of FSHD xenografts, where SLC34A2 is present in about 1%-2% of FSHD-affected fibers (Mueller et al., Exp. Neurol. 320: 113011, 2019). Our research shows that SLC34A2 mRNA and protein are significantly increased in maturing FSHD myotube cultures compared to controls. These levels decrease when myotubes are exposed to putative FSHD therapeutics such as losmapimod and other p38 kinase inhibitors. Additionally, we can label SLC34A2-positive FSHD fibers in xenografts in situ with an antibody specific to the exposed extracellular domain of SLC34A2 tagged with IR-647. This opens the prospect of tracking disease progression and the efficacy of different experimental therapies for FSHD in the same individuals over time, without the need for muscle biopsies. Support from SOLVE FSHD and the FSHD Society and stipends to MT from the NIH (5T32GM008181, PIs M. Trudeau and M. Rizzo, and 2T32AR007592, PI. A. Kontrogianni-Konstantopoulos). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.