Tamoxifen treatment fails to improve muscle dysfunction in a model of recessive RYR1-linked centronuclear myopathy.

Centronuclear myopathies (CNMs) are rare congenital muscle disorders with no effective treatment. Previous studies showed that tamoxifen improved muscle function in mice modeling CNMs caused by variants in MTM1, BIN1 and DNM2. Here, we investigated whether tamoxifen administration improves muscle function and pathology in the severe recessive Ryr1TM/indel mouse model of RYR1-related CNM. Contractile performance, histological analyses and protein levels were assessed in Ryr1TM/indel mice and control littermates (wild type) treated with either a tamoxifen-enriched diet (65 mg/kg of food) or a control diet for 5 weeks, beginning at 3 weeks of age. Ryr1TM/indel mice displayed muscle weakness, reduced myofiber size and a high number of fibers with nuclei in abnormal position, regardless of the treatment. Force production during repeated contractions was reduced in tamoxifen-treated Ryr1TM/indel mice compared to that in untreated Ryr1TM/indel mice. The levels of CNM proteins (DNM2 and BIN1) were unchanged following the treatment. Tamoxifen did not improve muscle dysfunction, atrophy or histological hallmarks in Ryr1TM/indel mice. Our data indicate that tamoxifen supplementation is not beneficial and may negatively impact muscle function in this model of CNM, suggesting limited therapeutic value for patients with RYR1 mutations.