CONGENITAL MYOPATHIES: CENTRONUCLEAR AND OTHERS

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are spectra of the same disease affecting muscle, platelets, spleen, and skin. TAM and STRMK arise from gain-of-function mutations in STIM1 or ORAI1, both encoding key regulators of Ca2+ homeostasis, and mutations in either gene results in excessive Ca2+ entry. To elucidate the physiological consequences of STIM1 over-activation, we generated a murine model harboring the most common TAM/STRMK mutation and characterized the phenotype at the histological, ultrastructural, metabolic, physiological, and functional level. In accordance with the clinical picture of TAM/STRMK, the Stim1R304W/+ mice manifested muscle weakness, thrombocytopenia, skin and eye anomalies, and spleen dysfunction, as well as additional features not yet observed in patients such as abnormal bone architecture and immune system dysregulation. In situ force measurements of the Stim1R304W/+ tibialis anterior revealed a reduction of the specific force, and we also measured sustained muscle contraction upon stimulation, demonstrating delayed muscle relaxation. Histological and ultrastructural analyses of Stim1R304W/+ tibialis anterior, soleus and gastrocnemius disclosed mild dystrophic features including internalized nuclei, regenerating fibers, fibrosis, and inflammation, fibers with high Ca2+ content, and swollen mitochondria. Tubular aggregates, the histopathological hallmark of TAM/STRMK were however not seen, demonstrating that they do no contribute to disease development. Ca2+ measurements on differentiated Stim1R304W/+ myotubes revealed elevated basal Ca2+ levels and an increased extracellular Ca2+ entry despite normal Ca2+ stores. Altogether, the Stim1R304W/+ mice recapitulate the main clinical features of TAM/STRMK, and provide insight into the pathophysiological effect STIM1 over-activation and aberrant Ca2+ homeostasis in different cells, tissues, and organs.