Protein Phosphorylation Alterations in Myotonic Dystrophy Type 1: A Systematic Review

Abstract

Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and weakness, and multisystemic dysfunctions. This disorder is caused by an abnormal expansion of the CTG triplet at the DMPK gene that, when transcribed to expanded mRNA, can lead to RNA toxic gain of function, alternative splicing impairments, and dysfunction of different signaling pathways, many regulated by protein phosphorylation. In order to deeply characterize the protein phosphorylation alterations in DM1, a systematic review was conducted through PubMed and Web of Science databases. From a total of 962 articles screened, 41 were included for qualitative analysis, where we retrieved information about total and phosphorylated levels of protein kinases, protein phosphatases, and phosphoproteins in DM1 human samples and animal and cell models. Twenty-nine kinases, 3 phosphatases, and 17 phosphoproteins were reported altered in DM1. Signaling pathways that regulate cell functions such as glucose metabolism, cell cycle, myogenesis, and apoptosis were impaired, as seen by significant alterations to pathways such as AKT/mTOR, MEK/ERK, PKC/CUGBP1, AMPK, and others in DM1 samples. This explains the complexity of DM1 and its different manifestations and symptoms, such as increased insulin resistance and cancer risk. Further studies can be done to complement and explore in detail specific pathways and how their regulation is altered in DM1, to find what key phosphorylation alterations are responsible for these manifestations, and ultimately to find therapeutic targets for future treatments.

Is There a Causal Connection? Mendelian Randomization Analysis of Muscular Dystrophies and Non-Alcoholic Fatty Liver Diseases

“…Secondly, it has been suggested that abnormal liver tests in MD may result from diminished contractility of the intrahepatic bile ducts, leading to impaired bile excretion and potential obstruction (34). Furthermore, key anabolic pathways involved in regulating glucose uptake, glycogen storage, and protein synthesis, such as the AKT/mTOR pathway, are often disrupted in MD (35). These disruptions elevate the risk of IR and NAFLD/NASH, contributing to increased reactive oxygen species production in hepatocytes (36).…”

Curriculum vitae of CUG binding protein 1 (CELF1) in homeostasis and diseases: a systematic review

“…Myotonic dystrophy is an autosomal dominant genetic disorder that impacts various organ systems, encompassing the skeletal muscles, heart, and brain [ 28 – 31 ]. Specifically, DM1 arises from an aberrant expansion of microsatellite DNA, leading to the sequestration of non-coding RNA products by RNA splicing factors [ 32 , 33 ].…”