Biology subjects

Ravel-Chapuis, A.

Publications and source records attributed to Ravel-Chapuis, A..

3 recordsLinked to original sources

bioRxiv2025

Acute AMPK activation does not adequately stimulate insulin signaling in skeletal muscle models of Myotonic Dystrophy Type 1

Myotonic Dystrophy Type 1 (DM1) is a multisystemic neuromuscular disorder characterized by skeletal muscle weakness, muscle atrophy, myotonia, cognitive impairments, gastrointestinal complications, and insulin resistance. While insulin resistance is well characterized in type 2 diabetes, its pathomechanism in DM1 remains unclear. Our study aims to elucidate the pathomechanism of insulin resistance in DM1 and how the pathway responds to AMPK stimulation. Proteomic analysis from sedentary wildtype and sedentary HSA-LR mice, a common DM1 mouse model, revealed downregulation of the AMPK-PGC-1 axis. Analysis of sedentary HSA-LR mice and exercised HSA-LR mice revealed activation of the AMPK-PGC-1 axis in exercised animals. To investigate this pathway, we treated WT and HSA-LR mice with the AMPK activator AICAR to examine the impact of AMPK stimulation on insulin signaling in DM1. This revealed impaired responses in the insulin pathway activation in the HSA-LR mice. Next, we examined whether these differences extended to a human model by treating control and DM1 myotubes with insulin and/or AICAR. In DM1 myotubes, both treatments produced dampened responses of key insulin signaling intermediates compared to controls. Taken together, these results suggest impaired activation of insulin signaling pathways in DM1 models and confirm the presence of insulin resistance with an impaired response to acute AMPK stimulation.

molecular biology↗

bioRxiv2022

LRRK2 Phosphorylates Neuronal Elav RNA-Binding Proteins to RegulatePhenotypes Relevant to Parkinson's Disease

Parkinsons disease (PD) is characterized by accumulation of -synuclein and the loss of dopaminergic neurons. Mutations which cause an increase in the kinase activity of Leucine-Rich-Repeat Kinase-2 (LRRK2) are a major inherited cause of PD. Research continues to determine which targets LRRK2 phosphorylates to cause disease. Polymorphisms in the locus of ELAVL4, an RNA-binding protein are a risk-factor for Parkinsons disease and an ELAV family member was identified in Drosophila as required for pathology instigated by human mutant LRRK2. We discovered that three neuronal ELAVs including ELAVL4 (also known as HuD) are phosphorylated by LRRK2. This controls binding of neuronal ELAVs to mRNA and their post- transcriptional regulation of mRNA abundance and splicing in neuronal cell lines and the mouse midbrain. LRRK2 G2019S functionally inhibits neuronal ELAVs effects on mRNA abundance, while enhancing their effects on mRNA splicing. The combination of LRRK2 G2019S and ELAVL4-/- causes accumulation of LRRK2 and -synuclein, loss of dopaminergic neurons and motor deficits. Targets of neuronal ELAVs are also selectively misregulated in cells and tissues of PD patients. Together, this suggests that misregulation of neuronal ELAVs, triggered by LRRK2 mutations may contribute to the characteristic pathology of Parkinsons disease. Brief SummaryLRRK2, a kinase linked to Parkinsons disease, phosphorylates the neuronal ELAV RNA-binding proteins to aggravate key hallmarks of Parkinsons disease including accumulation of -synuclein and motor deficits in mice.

cell biology↗

bioRxiv2022

Pharmacological inhibition of HDAC6 downregulates TGF-β via Smad2/3 acetylation and improves dystrophin-deficient muscles.

Abstract / SummaryThe absence of dystrophin in Duchenne muscular dystrophy (DMD) disrupts the dystrophin dystroglycan glycoprotein complex (DGC) resulting in fibers fragility and atrophy, associated with fibrosis and microtubules and neuromuscular junction (NMJ) disorganization. The specific non-conventional cytoplasmic histone deacetylase 6 (HDAC6) was previously shown to regulate acetylcholine receptor distribution and muscle atrophy. Here we show that administration of the HDAC6 specific inhibitor tubastatin A to the DMD mouse model mdx improves muscle strength, restores microtubules, NMJ and DGC organization, and reduces muscle atrophy and fibrosis. These effects involve the known action of HDAC6 on microtubules acetylation and muscle atrophy but also involve a yet undiscovered action of HDAC6 on transforming growth factor beta (TGF-{beta}) signaling. Conversely, to inhibitors of nuclear HDACs that regulate TGF-{beta} signaling via the activation of Follistatin expression, HDAC6 inhibition acts downstream of TGF-{beta} ligands and receptors by increasing Smad2/3 acetylation in the cytoplasm which in turn inhibits its phosphorylation and transcriptional activity.

physiology↗