In vivo RyR1 reduction in muscle triggers a core-like myopathy

Acta Neuropathologica Communications

Colline Sanchez¹  Candice Kutchukian¹  Vincent Jacquemond¹  Daniel Metzger²  David Bendahan³  Benoit Giannesini³  Clara Franzini Armstrong⁴  Anne Petiot⁵  Mathilde Chivet⁵  Lauriane Travard⁵  Julie Brocard⁵  Julien Fauré⁵  Isabelle Marty⁵  Mathilde Beaufils⁵  John Rendu⁵  Laurent Pelletier⁵  Diane Giovannini⁵  Norma B. Romero⁶ 

[1] CNRS UMR5310, INSERM U1217, Institut NeuroMyoGene, University Lyon I, Lyon, France;CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, University Strasbourg, Illkirch, France;CNRS, CRMBM, Aix-Marseille Univ, Marseille, France;Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA;INSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble Alpes, Bat EJ Safra, Chemin Fortuné Ferrini, La Tronche, Grenoble, France;Neuromuscular Morphology Unit, Center for Research in Myology, Myology Institute, Sorbonne University, GH Pitié-Salpêtrière, Paris, France;

关键词: Ryanodine receptor;    Calcium;    Skeletal muscle;    Excitation–contraction coupling;    Congenital myopathies;    Central core disease;    Dusty core disease;    Mouse model;   

DOI  :  10.1186/s40478-020-01068-4

来源: Springer

【 摘 要 】

Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction.

【 授权许可】

CC BY