Pathophysiological Effects of Overactive STIM1 on Murine Muscle Function and Structure

Store-operated Ca(2+) entry (SOCE) is a ubiquitous mechanism regulating extracellular Ca(2+) entry to control a multitude of Ca(2+)-dependent signaling pathways and cellular processes. SOCE relies on the concerted activity of the reticular Ca(2+) sensor STIM1 and the plasma membrane Ca(2+) channel ORAI1, and dysfunctions of these key factors result in human pathologies. STIM1 and ORAI1 gain-of-function (GoF) mutations induce excessive Ca(2+) influx through SOCE over-activation, and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterized by muscle weakness and additional multi-systemic signs affecting growth, platelets, spleen, skin, and intellectual abilities. In order to investigate the pathophysiological effect of overactive SOCE on muscle function and structure, we combined transcriptomics with morphological and functional studies on a TAM/STRMK mouse model. Muscles from Stim1(R304W/+) mice displayed aberrant expression profiles of genes implicated in Ca(2+) handling and excitation-contraction coupling (ECC), and in vivo investigations evidenced delayed muscle contraction and relaxation kinetics. We also identified signs of reticular stress and abnormal mitochondrial activity, and histological and respirometric analyses on muscle samples revealed enhanced myofiber degeneration associated with reduced mitochondrial respiration. Taken together, we uncovered a molecular disease signature and deciphered the pathomechanism underlying the functional and structural muscle anomalies characterizing TAM/STRMK.