Molecular mechanisms of muscle atrophy in myotonic dystrophies

Abstract

Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are multisystemic diseases that primarily affect skeletal muscle, causing myotonia, muscle atrophy, and muscle weakness. DM1 and DM2 pathologies are caused by expansion of CTG and CCTG repeats in non-coding regions of the genes encoding myotonic dystrophy protein kinase (DMPK) and zinc finger protein 9 (ZNF9) respectively. These expansions cause DM pathologies through accumulation of mutant RNAs that alter RNA metabolism in patients' tissues by targeting RNA-binding proteins such as CUG-binding protein 1 (CUGBP1) and Muscle blind-like protein 1 (MBNL1). Despite overwhelming evidence showing the critical role of RNA-binding proteins in DM1 and DM2 pathologies, the downstream pathways by which these RNA-binding proteins cause muscle wasting and muscle weakness are not well understood. This review discusses the molecular pathways by which DM1 and DM2 mutations might cause muscle atrophy and describes progress toward the development of therapeutic interventions for muscle wasting and weakness in DM1 and DM2. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Keywords: CUG/CCUG repeats; Muscle atrophy; Myotonic dystrophy type 1; Myotonic dystrophy type 2; Therapeutic approaches.

Figure 1. Model showing molecular pathways by which mutant DMPK mRNA might cause muscle atrophy and muscle weakness in DM1

The mutant CUG repeats reduce activity of MBNL1, increase total levels of CUGBP1, and increase levels of CUGBP1 that is not phosphorylated at S302, which represses protein translation in stress granules of DM1 cells. As a consequence, splicing and translation of mRNAs are mis-regulated in DM1 muscle, resulting in muscle atrophy and weakness.

Figure 2. A hypothetical model showing the proteins and pathways by which mutant CCUG repeats might cause muscle atrophy in DM2 muscle

Intron 1 of the ZNF9 gene containing expanded CCTG repeats is shown in the blue box, other introns are shown in green, and exons are shown in black. ZNF9 controls translation of TOP proteins involved in the translational machinery. Reduced levels of ZNF9 in patients with DM2 might cause a reduction in the expression of TOP proteins, leading to a reduction in the rate of global protein synthesis and resulting in muscle atrophy. Dysfunction of proteasomes, increased expression of CUGBP1, and a reduction in MBNL1 activity might also contribute to muscle atrophy in DM2.

Figure 3. Model showing two therapeutic approaches to correct muscle pathology in DM1

In the first approach, ASOs reduce the level of mutant DMPK mRNA leading to a correction of muscle pathology. The second approach uses GSK3β inhibitors to normalize GSK3β, which is activated by the mutant CUG repeats. These inhibitors correct the activity of CUGBP1 and increase the number of myogenic satellite cells. The inhibitors of GSK3β reduce myotonia, increase grip strength, and reduce DM1 muscle histopathology.