Aberrant insulin receptor expression is associated with insulin resistance and skeletal muscle atrophy in myotonic dystrophies

Abstract

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant multisystemic disorders linked to two different genetic loci and characterized by several features including myotonia, muscle atrophy and insulin resistance. The aberrant alternative splicing of insulin receptor (IR) gene and post-receptor signalling abnormalities have been associated with insulin resistance, however the precise molecular defects that cause metabolic dysfunctions are still unknown. Thus, the aims of this study were to investigate in DM skeletal muscle biopsies if beyond INSR missplicing, altered IR protein expression could play a role in insulin resistance and to verify if the lack of insulin pathway activation could contribute to skeletal muscle wasting. Our analysis showed that DM skeletal muscle exhibits a lower expression of the insulin receptor in type 1 fibers which can contribute to the defective activation of the insulin pathway. Moreover, the aberrant insulin signalling activation leads to a lower activation of mTOR and to an increase in MuRF1 and Atrogin-1/MAFbx expression, possible explaining DM skeletal muscle fiber atrophy. Taken together our data indicate that the defective insulin signalling activation can contribute to skeletal muscle features in DM patients and are probably linked to an aberrant specific-fiber type expression of the insulin receptor.

Insulin Signaling as a Key Moderator in Myotonic Dystrophy Type 1

“…This switch toward IR-A was recaptured in muscle cultures from fibroblasts, which also demonstrated decreased insulin mediated glucose uptake (52). Dysregulated splicing of the INSR pre-mRNA toward the embyronal IR-A isoform in muscle cells was confirmed in subsequent studies (150, 152, 153). Splicing dysregulation of IR pre-mRNA was independent of fiber type (i.e., type 1 or type 2 muscle fibers), and of muscle location (i.e., proximal vs. distal) (150, 152).…”

“…Splicing dysregulation of IR pre-mRNA was independent of fiber type (i.e., type 1 or type 2 muscle fibers), and of muscle location (i.e., proximal vs. distal) (150, 152). Moreover, IR expression at the protein level occurs only in type 1 muscle cells (153). This recent study by Renna et al also demonstrated that in DM1 muscle cells, insulin-dependent activation of signaling pathways IRS1-AKT/PKB and Ras-ERK was decreased in comparison to controls (153).…”

“…Moreover, IR expression at the protein level occurs only in type 1 muscle cells (153). This recent study by Renna et al also demonstrated that in DM1 muscle cells, insulin-dependent activation of signaling pathways IRS1-AKT/PKB and Ras-ERK was decreased in comparison to controls (153). The results of this study suggest a link between dysregulated IR splicing and previous findings of decreased insulin mediated glucose uptake and protein synthesis in myotubes differentiated from fetal DM1 muscle myoblasts in comparison to healthy control myoblasts (148).…”

High Prevalence and Gender-Related Differences of Gastrointestinal Manifestations in a Cohort of DM1 Patients: A Perspective, Cross-Sectional Study

“…To clarify this issue, we are going to evaluate in a further study prevalence and predictors of NAFLD in our cohort of DM1 patients, in comparison to a non-DM1-NAFLD cohort. NAFLD is strongly associated with insulin resistance and type 2 diabetes (23): both these conditions are frequent features also in DM1 (24), being likely related to the aberrant expression of the insulin receptor in the peripheral tissues (25)(26)(27) and/or to the presence of other post-receptor signaling abnormalities in DM1 tissues (28).…”

Muscle single-cell analysis reveals that RNA foci accumulation is linked to muscle dysfunction in patients with myotonic dystrophy type I

“…The altered transcription of these genes in DM1 has been related to several symptoms of the disease. Thus, INSR and CLCN1 misregulation are associated with insulin resistance (Renna et al, 2019) and myotonia (Charlet-B. et al, 2002), respectively, and ATP2A1 might impair calcium homeostasis in skeletal muscle (Kimura et al, 2005).…”