Circulating MYOM3 fragments reflect disease severity and therapeutic efficacy in tubular aggregate myopathy and Stormorken syndrome

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by muscle weakness, thrombocytopenia, spleen anomalies and short stature. They are due to mutations affecting the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1 and leading to aberrant Ca2+ homeostasis. Therapeutic approaches aiming to rebalance intracellular Ca2+ levels largely rescued the multi-systemic phenotype in Stim1R304W/+ mice harboring the most common TAM/STRMK mutation. However, the currently used biomarkers to follow disease progression are costly and inadequate for longitudinal studies. Here, we investigated the suitability of MYOM3 to serve as a robust blood-based biomarker for TAM/STRMK. Using only minimal blood volumes, we detected highly elevated circulating MYOM3 levels in plasma samples from Stim1R304W/+ mice and TAM/STRMK patients with different mutations, and we found that the MYOM3 levels were normalized in Stim1R304W/+ mice undergoing efficient therapies. We also identified skeletal muscle as the primary source of circulating MYOM3, a structural protein of the contractile unit in myofibers, and uncovered that MYOM3 is primarily expressed in regenerating muscle fibers and in fast-twitch type IIa fibers. Overall, this work emphasizes the utility of MYOM3 as a minimally-invasive biomarker for disorders involving myofiber degeneration, and highlights the ability of MYOM3 to detect early muscle dysfunction in TAM/STRMK and evaluate therapeutic efficiency.