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.

Introduction: Chronic antibody-mediated rejection (cAMR) has very few effective therapeutic options. Interleukin-6 is an attractive target because it is involved in inflammation and humoral immunity. Therefore, the use of tocilizumab (anti-IL6 receptor, TCZ) is a potential valuable therapeutic option to treat cABMR in kidney-transplant (KT) recipients.Materials and Methods: This single-center retrospective study included all KT recipients that received monthly TCZ infusions in the setting of cABMR, between August 2018 and July 2021. We assessed 12-month renal function and KT histology during follow-up.Results: Forty patients were included. At 12-months, eGFR was not significantly different, 41.6 ± 17 vs. 43 ± 17 mL/min/1.73 m2 (p = 0.102) in patients with functional graft. Six patients (15%) lost their graft: their condition was clinically more severe at the time of first TCZ infusion. Histological follow-up showed no statistical difference in the scores of glomerulitis, peritubular capillaritis, and interstitial fibrosis/tubular atrophy (IFTA). Chronic glomerulopathy score however, increased significantly over time; conversely arteritis and inflammation in IFTA ares improved in follow-up biopsies.Conclusion: In our study, the addition of TCZ prevented clinical and histological worsening of cABMR in KT recipients, except for more severely ill patients. Randomized studies are needed to clarify the risk/benefit of TCZ in cABMR.