title: Calcium homeostasis alterations in a mouse model of the Dynamin 2-related centronuclear myopathy.
abstract: Autosomal dominant centronuclear myopathy (CNM) is a rare congenital myopathy characterized by centrally located nuclei in muscle fibers. CNM results from mutations in the gene encoding dynamin 2 (DNM2), a large GTPase involved in endocytosis, intracellular membrane trafficking, and cytoskeleton regulation. We developed a knock-in mouse model expressing the most frequent DNM2-CNM mutation; i.e. the KI-Dnm2R465Wmodel. Heterozygous (HTZ) KI-Dnm2 mice progressively develop muscle atrophy, impairment of contractile properties, histopathological abnormalities, and elevated cytosolic calcium concentration. Here, we aim at better characterizing the calcium homeostasis impairment in extensor digitorum longus (EDL) and soleus muscles from adult HTZ KI-Dnm2 mice. We demonstrate abnormal contractile properties and cytosolic Ca2+concentration in EDL but not soleus muscles showing that calcium impairment is correlated with muscle weakness and might be a determinant factor of the spatial muscle involvement. In addition, the elevated cytosolic Ca2+concentration in EDL muscles is associated with an increased sarcolemmal permeability to Ca2+and releasable Ca2+content from the sarcoplasmic reticulum. However, amplitude and kinetics characteristics of the calcium transient appear unchanged. This suggests that calcium defect is probably not a primary cause of decreased force generation by compromised sarcomere shortening but may be involved in long-term deleterious consequences on muscle physiology. Our results highlight the first pathomechanism which may explain the spatial muscle involvement occurring in DNM2-related CNM and open the way toward development of a therapeutic approach to normalize calcium content.
authors.affiliation: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes 44200, France.
authors.forename: Bodvaël
authors.initials: B
authors.lastname: Fraysse
authors.affiliation: INSERM, UMR_S1166, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris 75013, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.affiliation: Research Center for Myology, UPMC Univ Paris 06 and INSERM UMR_S974, CNRS FRE 3617, Institute of Myology, Paris 75013, France m.bitoun@institut-myologie.org.
authors.forename: Marc
authors.identifier: http://orcid.org/0000-0002-4188-7918
authors.initials: M
authors.lastname: Bitoun
keywords: Calcium; Centronuclear myopathy; Dynamin 2; Knock-in mouse model