GSK3β is a new therapeutic target for myotonic dystrophy type 1

Figures & data

Figure 1. Toxic events caused by mutant CUG repeats in DM1 cells and possible therapeutic approaches for their correction. Mutant CUG repeats cause three toxic molecular events: (1) sequestration of MBNL1, (2) higher levels of CUGBP1, leading to elevation of the active form of CUGBP1 (CUGBP1^ACT), and (3) elevation of active GSK3β, which reduces cyclin D3 and converts a portion of CUGBP1^ACT to CUGBP1^REP. Thus, both CUGBP1 forms are elevated in DM1. Reduced MBNL1 and increased CUGBP1^ACT lead to deregulation of mRNA splicing, translation, and stability. Futhermore, increased CUGBP1^REP may reduce mRNA translation in stress granules. Taken together, these molecular changes lead to myotonia, weakness, and muscle atrophy. Administration of GSK3β inhibitors reduces DM1 muscle histopathology, weakness, and myotonia similar to degradation of mutant CUG repeats by AONs.

Figure 2. Correction of muscle histopathology in HSA^LR mice treated with GSK3 inhibitors, namely lithium and TDZD-8. (A) Hematoxylin and eosin staining of muscle sections (gastrocnemius) from age-matched 6-mo-old WT, untreated HSA^LR mice, and lithium-treated HSA^LR mice. Internal nuclei in the muscle of untreated HSA^LR mice are indicated by asterisks. (B) Lithium reduces myofiber size variability in HSA^LR mice. Myofiber area was compared in gastrocnemius from age-matched 6-mo-old WT mice and HSA^LR mice untreated and treated for 2 weeks with lithium. The y-axis shows the average myofiber area in pixels. p < 3.36 × 10⁻¹⁶ (untreated HSA^LR mice vs. WT mice); p < 1.10 × 10⁻⁷ (treated vs. untreated HSA^LR mice). (C) TDZD-8 treatment reduces myofiber size variability in HSA^LR muscle. Myofiber area was increased in 4-mo-old HSA^LR mice relative to WT mice (***p < 5.88 × 10⁻⁶). The myofiber area was reduced in HSA^LR mice after TDZD-8 treatment. *p < 0.02677 (treated HSA^LR mice vs. untreated). (D) Treatment of HSA^LR mice with TDZD-8 reduces the number of central nuclei in the skeletal muscle (gastrocnemius) of HSA^LR mice. The number of central nuclei was counted in six randomly selected 20 × views and the average values are shown. The average number of central nuclei per view was increased in HSA^LR mice (***p < 4.616 × 10⁻⁸) relative to WT mice. However, treatment with TDZD-8 reduced the number of central nuclei. ***p < 0.000387 (treated HSA^LR mice vs. untreated).