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

Area of Science:

• Neurology
• Genetics
• Muscle Biology

Background:

• Centronuclear myopathies (CNMs) are rare genetic muscle disorders lacking effective treatments.
• Tamoxifen has previously shown benefits in mouse models of CNM caused by MTM1, BIN1, and DNM2 gene variants.

Purpose of the Study:

• To investigate the efficacy of tamoxifen in a severe recessive RYR1-related CNM mouse model (Ryr1TM/indel).
• To assess tamoxifen's impact on muscle function, pathology, and protein levels in RYR1-related CNM.

Main Methods:

• Ryr1TM/indel mice and wild-type littermates were fed a tamoxifen-enriched diet or a control diet for 5 weeks.
• Evaluated muscle contractile performance, performed histological analyses, and measured protein levels.

Main Results:

• Ryr1TM/indel mice exhibited inherent muscle weakness, reduced myofiber size, and abnormal nuclear positioning, irrespective of tamoxifen treatment.
• Tamoxifen treatment led to reduced force production during repeated contractions in Ryr1TM/indel mice.
• Tamoxifen did not alter the levels of key CNM proteins (DNM2, BIN1) and did not improve muscle dysfunction or pathology.

Conclusions:

• Tamoxifen supplementation demonstrated no benefit and potentially impaired muscle function in the Ryr1TM/indel mouse model of CNM.
• These findings suggest limited therapeutic potential for tamoxifen in patients with RYR1 mutations causing CNM.