In vivo RyR1 reduction in muscle triggers a core-like myopathy
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RESEARCH
In vivo RyR1 reduction in muscle triggers a core‑like myopathy Laurent Pelletier1†, Anne Petiot1†, Julie Brocard1, Benoit Giannesini2†, Diane Giovannini1†, Colline Sanchez3, Lauriane Travard1, Mathilde Chivet1, Mathilde Beaufils1, Candice Kutchukian3, David Bendahan2, Daniel Metzger4, Clara Franzini Armstrong5, Norma B. Romero6, John Rendu1, Vincent Jacquemond3, Julien Fauré1 and Isabelle Marty1*
Abstract 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. Keywords: Ryanodine receptor, Calcium, Skeletal muscle, Excitation–contraction coupling, Congenital myopathies, Central core disease, Dusty core disease, Mouse model
Introduction One key step for skeletal muscle contraction is the intracellular calcium release performed by the sarcoplasmic reticulum calcium channel ryanodine receptor (RyR1) *Correspondence: isabelle.marty@univ‑grenoble‑alpes.fr † Laurent Pelletier and Anne Petiot have contributed equally. † Benoit Giannesini, Diane Giovannini, and Colline Sanchez have contributed equally. 1 INSERM, GIN‑U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble Alpes, Bat EJ Safra, Chemin Fortuné Ferrini, La Tronche, Grenoble, France Full list of author information is available at the end of the article
during the excitation–contraction coupling process. RyR1 is the core of the Calcium Release Complex (CRC), anchored both in the sarcoplasmic reticulum (SR) membrane and the T-tubule membrane, in a specific region of the muscle called the triad where these two membranes are in close apposition. Additional proteins are associated with RyR1 to form the CRC, including the voltage-activated plasma membrane calcium channel dihydropyridine receptor
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