Fiche publication
Date publication
juillet 2021
Journal
Cells
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GENY Bernard
Tous les auteurs :
Silva-Rojas R, Charles AL, Djeddi S, Geny B, Laporte J, Böhm J
Lien Pubmed
Résumé
Store-operated Ca entry (SOCE) is a ubiquitous mechanism regulating extracellular Ca entry to control a multitude of Ca-dependent signaling pathways and cellular processes. SOCE relies on the concerted activity of the reticular Ca sensor STIM1 and the plasma membrane Ca channel ORAI1, and dysfunctions of these key factors result in human pathologies. and gain-of-function (GoF) mutations induce excessive Ca 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 mice displayed aberrant expression profiles of genes implicated in Ca 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.
Mots clés
STIM2, York platelet syndrome, calcium, congenital myopathy, muscle weakness, neuromuscular disorder
Référence
Cells. 2021 07 8;10(7):
