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GSK3β is a new therapeutic target for myotonic dystrophy type 1.

Wei C, Jones K, Timchenko NA, Timchenko L - Rare Dis (2013)

Bottom Line: The mutant CUG repeats increase the levels of CUGBP1 protein and inhibit Ser302 phosphorylation, leading to the accumulation of CUGBP1 isoforms that repress translation (i.e., CUGBP1(REP)).Elevation of CUGBP1(REP) in DM1 is caused by increased GSK3β kinase, which reduces the cyclin D3-CDK4 pathway and subsequent phosphorylation of CUGBP1 at Ser302.These findings demonstrate that GSK3β is a novel therapeutic target for treating DM1.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics; Baylor College of Medicine; Houston, TX USA.

ABSTRACT
Myotonic dystrophy type 1 (DM1), an incurable, neuromuscular disease, is caused by the expansion of CTG repeats within the 3' UTR of DMPK on chromosome 19q. In DM1 patients, mutant DMPK transcripts deregulate RNA metabolism by altering CUG RNA-binding proteins. Several approaches have been proposed for DM1 therapy focused on specific degradation of the mutant CUG repeats or on correction of RNA-binding proteins, affected by CUG repeats. One such protein is CUG RNA-binding protein (CUGBP1). The ability of CUGBP1 to increase or inhibit translation depends on phosphorylation at Ser302, which is mediated by cyclin D3-CDK4. The mutant CUG repeats increase the levels of CUGBP1 protein and inhibit Ser302 phosphorylation, leading to the accumulation of CUGBP1 isoforms that repress translation (i.e., CUGBP1(REP)). Elevation of CUGBP1(REP) in DM1 is caused by increased GSK3β kinase, which reduces the cyclin D3-CDK4 pathway and subsequent phosphorylation of CUGBP1 at Ser302. In this review, we discuss our recent discovery showing that correction of GSK3β activity in the DM1 mouse model (i.e., HSA(LR) mice) reduces DM1 muscle pathology. These findings demonstrate that GSK3β is a novel therapeutic target for treating DM1.

No MeSH data available.


Related in: MedlinePlus

Figure 2. Correction of muscle histopathology in HSALR 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 HSALR mice, and lithium-treated HSALR mice. Internal nuclei in the muscle of untreated HSALR mice are indicated by asterisks. (B) Lithium reduces myofiber size variability in HSALR mice. Myofiber area was compared in gastrocnemius from age-matched 6-mo-old WT mice and HSALR 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 HSALR mice vs. WT mice); p < 1.10 × 10−7 (treated vs. untreated HSALR mice). (C) TDZD-8 treatment reduces myofiber size variability in HSALR muscle. Myofiber area was increased in 4-mo-old HSALR mice relative to WT mice (***p < 5.88 × 10−6). The myofiber area was reduced in HSALR mice after TDZD-8 treatment. *p < 0.02677 (treated HSALR mice vs. untreated). (D) Treatment of HSALR mice with TDZD-8 reduces the number of central nuclei in the skeletal muscle (gastrocnemius) of HSALR 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 HSALR 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 HSALR mice vs. untreated).
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Figure 2: Figure 2. Correction of muscle histopathology in HSALR 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 HSALR mice, and lithium-treated HSALR mice. Internal nuclei in the muscle of untreated HSALR mice are indicated by asterisks. (B) Lithium reduces myofiber size variability in HSALR mice. Myofiber area was compared in gastrocnemius from age-matched 6-mo-old WT mice and HSALR 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 HSALR mice vs. WT mice); p < 1.10 × 10−7 (treated vs. untreated HSALR mice). (C) TDZD-8 treatment reduces myofiber size variability in HSALR muscle. Myofiber area was increased in 4-mo-old HSALR mice relative to WT mice (***p < 5.88 × 10−6). The myofiber area was reduced in HSALR mice after TDZD-8 treatment. *p < 0.02677 (treated HSALR mice vs. untreated). (D) Treatment of HSALR mice with TDZD-8 reduces the number of central nuclei in the skeletal muscle (gastrocnemius) of HSALR 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 HSALR 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 HSALR mice vs. untreated).

Mentions: Once alterations to the GSK3β pathway were discovered, we investigated whether GSK3 inhibitors can correct the pathology of DM1. Analysis of HSALR mice treated with inhibitors of GSK3, namely lithium and TDZD-8, showed that elevated GSK3β plays a crucial role in DM1 pathology. We found that both inhibitors significantly increased grip strength in HSALR mice and improved DM1 muscle histology.25 Moreover, treatment of HSALR mice with lithium or TDZD-8 significantly reduced variability in myofiber size (Fig. 2A-C), as well as the number of central nuclei in HSALR muscle25 (Fig. 2D). Based on these data, we concluded that the elevated GSK3β is the third major toxic event in DM1 pathogenesis (Fig. 1).


GSK3β is a new therapeutic target for myotonic dystrophy type 1.

Wei C, Jones K, Timchenko NA, Timchenko L - Rare Dis (2013)

Figure 2. Correction of muscle histopathology in HSALR 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 HSALR mice, and lithium-treated HSALR mice. Internal nuclei in the muscle of untreated HSALR mice are indicated by asterisks. (B) Lithium reduces myofiber size variability in HSALR mice. Myofiber area was compared in gastrocnemius from age-matched 6-mo-old WT mice and HSALR 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 HSALR mice vs. WT mice); p < 1.10 × 10−7 (treated vs. untreated HSALR mice). (C) TDZD-8 treatment reduces myofiber size variability in HSALR muscle. Myofiber area was increased in 4-mo-old HSALR mice relative to WT mice (***p < 5.88 × 10−6). The myofiber area was reduced in HSALR mice after TDZD-8 treatment. *p < 0.02677 (treated HSALR mice vs. untreated). (D) Treatment of HSALR mice with TDZD-8 reduces the number of central nuclei in the skeletal muscle (gastrocnemius) of HSALR 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 HSALR 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 HSALR mice vs. untreated).
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Figure 2: Figure 2. Correction of muscle histopathology in HSALR 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 HSALR mice, and lithium-treated HSALR mice. Internal nuclei in the muscle of untreated HSALR mice are indicated by asterisks. (B) Lithium reduces myofiber size variability in HSALR mice. Myofiber area was compared in gastrocnemius from age-matched 6-mo-old WT mice and HSALR 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 HSALR mice vs. WT mice); p < 1.10 × 10−7 (treated vs. untreated HSALR mice). (C) TDZD-8 treatment reduces myofiber size variability in HSALR muscle. Myofiber area was increased in 4-mo-old HSALR mice relative to WT mice (***p < 5.88 × 10−6). The myofiber area was reduced in HSALR mice after TDZD-8 treatment. *p < 0.02677 (treated HSALR mice vs. untreated). (D) Treatment of HSALR mice with TDZD-8 reduces the number of central nuclei in the skeletal muscle (gastrocnemius) of HSALR 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 HSALR 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 HSALR mice vs. untreated).
Mentions: Once alterations to the GSK3β pathway were discovered, we investigated whether GSK3 inhibitors can correct the pathology of DM1. Analysis of HSALR mice treated with inhibitors of GSK3, namely lithium and TDZD-8, showed that elevated GSK3β plays a crucial role in DM1 pathology. We found that both inhibitors significantly increased grip strength in HSALR mice and improved DM1 muscle histology.25 Moreover, treatment of HSALR mice with lithium or TDZD-8 significantly reduced variability in myofiber size (Fig. 2A-C), as well as the number of central nuclei in HSALR muscle25 (Fig. 2D). Based on these data, we concluded that the elevated GSK3β is the third major toxic event in DM1 pathogenesis (Fig. 1).

Bottom Line: The mutant CUG repeats increase the levels of CUGBP1 protein and inhibit Ser302 phosphorylation, leading to the accumulation of CUGBP1 isoforms that repress translation (i.e., CUGBP1(REP)).Elevation of CUGBP1(REP) in DM1 is caused by increased GSK3β kinase, which reduces the cyclin D3-CDK4 pathway and subsequent phosphorylation of CUGBP1 at Ser302.These findings demonstrate that GSK3β is a novel therapeutic target for treating DM1.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics; Baylor College of Medicine; Houston, TX USA.

ABSTRACT
Myotonic dystrophy type 1 (DM1), an incurable, neuromuscular disease, is caused by the expansion of CTG repeats within the 3' UTR of DMPK on chromosome 19q. In DM1 patients, mutant DMPK transcripts deregulate RNA metabolism by altering CUG RNA-binding proteins. Several approaches have been proposed for DM1 therapy focused on specific degradation of the mutant CUG repeats or on correction of RNA-binding proteins, affected by CUG repeats. One such protein is CUG RNA-binding protein (CUGBP1). The ability of CUGBP1 to increase or inhibit translation depends on phosphorylation at Ser302, which is mediated by cyclin D3-CDK4. The mutant CUG repeats increase the levels of CUGBP1 protein and inhibit Ser302 phosphorylation, leading to the accumulation of CUGBP1 isoforms that repress translation (i.e., CUGBP1(REP)). Elevation of CUGBP1(REP) in DM1 is caused by increased GSK3β kinase, which reduces the cyclin D3-CDK4 pathway and subsequent phosphorylation of CUGBP1 at Ser302. In this review, we discuss our recent discovery showing that correction of GSK3β activity in the DM1 mouse model (i.e., HSA(LR) mice) reduces DM1 muscle pathology. These findings demonstrate that GSK3β is a novel therapeutic target for treating DM1.

No MeSH data available.


Related in: MedlinePlus