Metabolic Alterations in Myotonic Dystrophy Type 1 and Their Correlation with Lipin

Abstract

Myotonic dystrophy type 1 (DM1) is an autosomal dominant hereditary and multisystemic disease, characterized by progressive distal muscle weakness and myotonia. Despite huge efforts, the pathophysiological mechanisms underlying DM1 remain elusive. In this review, the metabolic alterations observed in patients with DM1 and their connection with lipin proteins are discussed. We start by briefly describing the epidemiology, the physiopathological and systemic features of DM1. The molecular mechanisms proposed for DM1 are explored and summarized. An overview of metabolic syndrome, dyslipidemia, and the summary of metabolic alterations observed in patients with DM1 are presented. Patients with DM1 present clinical evidence of metabolic alterations, namely increased levels of triacylglycerol and low-density lipoprotein, increased insulin and glucose levels, increased abdominal obesity, and low levels of high-density lipoprotein. These metabolic alterations may be associated with lipins, which are phosphatidate phosphatase enzymes that regulates the triacylglycerol levels, phospholipids, lipid signaling pathways, and are transcriptional co-activators. Furthermore, lipins are also important for autophagy, inflammasome activation and lipoproteins synthesis. We demonstrate the association of lipin with the metabolic alterations in patients with DM1, which supports further clinical studies and a proper exploration of lipin proteins as therapeutic targets for metabolic syndrome, which is important for controlling many diseases including DM1.

Nuclear Envelope Alterations in Myotonic Dystrophy Type 1 Patient-Derived Fibroblasts

“…The precise molecular mechanism underlying DM1 is still elusive. The toxic gain of function of expanded CUG repeats of mutant DMPK mRNA and haploinsufficiency are two well accepted proposed mechanisms [ 6 ]. As a consequence, the protein levels of DMPK are found to be decreased in DM1 tissues [ 23 ].…”

“…Our results showed decreased DMPK intracellular protein levels in DM1 patient-derived fibroblasts ( Figure 1 ). Since the DMPK protein is encoded by the DMPK gene, which is abnormally expanded in the 3′UTR region in DM1, these mutant transcripts with abnormal CUG expansions are not efficiently transported to the cytoplasm and accumulate in cell nuclei; therefore, they are not translated into protein [ 6 , 10 , 23 , 30 , 31 ]. Thus, intracellular protein levels of DMPK are reduced in patients with DM1, regardless of the length of the CTG repeat, as shown in Figure 1 .…”

“…DM1 is characterized by a slowly progressing muscle weakness, loss of muscle mass and myotonia. Additionally, DM1 is also categorized as a multisystemic disease, affecting other organs, namely the eyes (cataracts), heart (conduction problems leading to cardiomyopathies) and respiratory system, and causing metabolic alterations (insulin insensitivity and diabetes) [ 3 , 4 , 5 , 6 ]. DM1 is a genetic disease caused by an abnormal unstable expansion of the CTG trinucleotide in the 3′UTR of the Myotonic Dystrophy Protein Kinase (DMPK) gene [ 1 , 7 ].…”

“…The central protein of DM1, DMPK, is a protein kinase that consists of seven distinct isoforms (DMPK A to G) in humans, which are generated by alternative splicing. DMPK’s subcellular localization is confined to either the endoplasmic reticulum or nuclear envelope (NE) (DMPK A and B), mitochondria (DMPK C and D) or cytoplasm (DMPK E, F and G) [ 6 , 8 , 9 ].…”

“…Several studies have been carried out to unravel the molecular mechanisms underlying this pathology. To date, there are three more consensual hypotheses explaining the pathogenesis of DM1: RNA toxic gain-of-function, haploinsufficiency of DMPK and rearrangement of the DM1 locus [ 6 , 10 , 11 , 12 ]. Despite the great deal of effort for unravelling the molecular mechanism underlying DM1, none of these hypotheses can explain all the multisystemic signs and symptoms.…”