The hallmarks of myotonic dystrophy type 1 muscle dysfunction

Abstract

Myotonic dystrophy type 1 (DM1) is the most prevalent form of muscular dystrophy in adults and yet there are currently no treatment options. Although this disease causes multisystemic symptoms, it is mainly characterised by myopathy or diseased muscles, which includes muscle weakness, atrophy, and myotonia, severely affecting the lives of patients worldwide. On a molecular level, DM1 is caused by an expansion of CTG repeats in the 3′ untranslated region (3′UTR) of the DM1 Protein Kinase (DMPK) gene which become pathogenic when transcribed into RNA forming ribonuclear foci comprised of auto complementary CUG hairpin structures that can bind proteins. This leads to the sequestration of the muscleblind‐like (MBNL) family of proteins, depleting them, and the abnormal stabilisation of CUGBP Elav‐like family member 1 (CELF1), enhancing it. Traditionally, DM1 research has focused on this RNA toxicity and how it alters MBNL and CELF1 functions as key splicing regulators. However, other proteins are affected by the toxic DMPK RNA and there is strong evidence that supports various signalling cascades playing an important role in DM1 pathogenesis. Specifically, the impairment of protein kinase B (AKT) signalling in DM1 increases autophagy, apoptosis, and ubiquitin–proteasome activity, which may also be affected in DM1 by AMP‐activated protein kinase (AMPK) downregulation. AKT also regulates CELF1 directly, by affecting its subcellular localisation, and indirectly as it inhibits glycogen synthase kinase 3 beta (GSK3β), which stabilises the repressive form of CELF1 in DM1. Another kinase that contributes to CELF1 mis‐regulation, in this case by hyperphosphorylation, is protein kinase C (PKC). Additionally, it has been demonstrated that fibroblast growth factor‐inducible 14 (Fn14) is induced in DM1 and is associated with downstream signalling through the nuclear factor κB (NFκB) pathways, associating inflammation with this disease. Furthermore, MBNL1 and CELF1 play a role in cytoplasmic processes involved in DM1 myopathy, altering proteostasis and sarcomere structure. Finally, there are many other elements that could contribute to the muscular phenotype in DM1 such as alterations to satellite cells, non‐coding RNA metabolism, calcium dysregulation, and repeat‐associated non‐ATG (RAN) translation. This review aims to organise the currently dispersed knowledge on the different pathways affected in DM1 and discusses the unexplored connections that could potentially help in providing new therapeutic targets in DM1 research.

Musashi-2 contributes to myotonic dystrophy muscle dysfunction by promoting excessive autophagy through miR-7 biogenesis repression

“…Muscle wasting is a critical symptom in DM1 patients, and multiple contributing factors have been proposed to explain muscle loss. 8 Several studies support a relevant role for hyperactivated autophagy. In a Drosophila DM1 model and DM1 myotubes, the autophagic flux is overactivated, and genetic or chemical blockade of this pathway, by mechanistic target of rapamycin kinase (mTOR) upregulation or chloroquine treatment, an autophagy blocker, improves muscle function and molecular markers of muscle atrophy.…”

Regulatory Potential of Competing Endogenous RNAs in Myotonic Dystrophies

“…Clinically, DM1 and DM2 are multisystem disorders characterized by myotonia, progressive muscle weakness, heart conduction defects, cognitive impairments, endocrine abnormalities, insulin resistance, cataracts, and gastrointestinal manifestations, with the symptoms being usually more severe in DM1 than in DM2. All the hallmarks of DMs, their clinical manifestations, and phenotypes, as well as various therapeutic perspectives, have been extensively reviewed [ 59 , 60 , 61 , 62 , 63 , 64 , 65 ]. Worthy of note is also an overview of miRNAs in the context of DM, as important roles of many miRNA have been linked with these diseases (comprehensively reviewed in [ 62 ]).…”

Cpy(a/t)(q/w)e D-Hexapeptides Bind CUG Repeats and Rescue Phenotypes of Myotonic Dystrophy Myoblasts and A Drosophila Model of the Disease

“…Symptoms of myotonia, muscle weakness, and muscular atrophy are the main features of DM1 1 , and the molecular contributions to these symptoms are numerous 10 . One of them is a delay in the process of muscle differentiation, which can be quanti ed as a reduction in the fusion index after the induction of the broblasts to myoblasts transdifferentiation 32 33 .…”

“…Human MBNL1 proteins are tissue-speci c CCCH zinc nger factors with crucial roles in the regulation of alternative splicing and alternative polyadenylation during development, in which it promotes a switch from fetal to adult patterns in a wide number of transcripts 7 8 9 . Although lack of MBNL1 function is one of the main molecular hallmarks of DM1 myopathy, many additional molecular contributors have been reported 10 . Hyperactivated GSKbeta and autophagy have been proposed to contribute to muscle atrophy in DM1 by stabilizing a repressive form of CELF1 alternative splicing regulator in the nucleus and downregulation of miR-7, a master regulator of autophagy, respectively 11 12,13 .…”