Resveratrol enhances splicing of insulin receptor exon 11 in myotonic dystrophy type 1 fibroblasts

Takarada, Toru; Nishida, Atsushi; Takeuchi, Atsuko; Lee, Tomoko; Takeshima, Yasuhiro; Matsuo, Masafumi

doi:10.1016/j.braindev.2014.11.001

Cited by 12 publications

(4 citation statements)

References 36 publications

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“…This result is not unexpected because resveratrol is known to be less effective in activating AMPK signalling in comparison with AICAR in mice (Ljubicic et al., 2014). Nonetheless, these effects observed in vivo are coherent with results from cell culture models showing that resveratrol can correct Insr and Ryr1 alternative splicing in DM1 fibroblasts (Takarada et al., 2015) and myotubes (Santoro et al., 2020), respectively, and suggest that resveratrol and other natural compounds activating AMPK could be of great therapeutic interest for DM1.…”

Section: Introductionsupporting

confidence: 77%

Pharmacological and exercise‐induced activation of AMPK as emerging therapies for myotonic dystrophy type 1 patients

Ravel‐Chapuis

Duchesne

Jasmin

2022

The Journal of Physiology

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Myotonic dystrophy type 1 (DM1) is a multisystemic disorder with variable clinical features. Currently, there is no cure or effective treatment for DM1. The disease is caused by an expansion of CUG repeats in the 3′ UTR of DMPK mRNAs. Mutant DMPK mRNAs accumulate in nuclei as RNA foci and trigger an imbalance in the level and localization of RNA‐binding proteins causing the characteristic missplicing events that account for the varied DM1 symptoms, a disease mechanism referred to as RNA toxicity. In recent years, multiple signalling pathways have been identified as being aberrantly regulated in skeletal muscle in response to the CUG expansion, including AMPK, a sensor of energy status, as well as a master regulator of cellular energy homeostasis. Converging lines of evidence highlight the benefits of activating AMPK signalling pharmacologically on RNA toxicity, as well as on muscle histology and function, in preclinical DM1 models. Importantly, a clinical trial with metformin, an activator of AMPK, resulted in functional benefits in DM1 patients. In addition, exercise, a known AMPK activator, has shown promising effects on RNA toxicity and muscle function in DM1 mice. Finally, clinical trials involving moderate‐intensity exercise also induced functional benefits for DM1 patients. Taken together, these studies clearly demonstrate the molecular, histological and functional benefits of AMPK activation and exercise‐based interventions on the DM1 phenotype. Despite these advances, several key questions remain; in particular, the extent of the true implication of AMPK in the observed beneficial improvements, as well as how, mechanistically, activation of AMPK signalling improves the DM1 pathophysiology.

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Section: Introductionsupporting

confidence: 77%

Pharmacological and exercise‐induced activation of AMPK as emerging therapies for myotonic dystrophy type 1 patients

Ravel‐Chapuis

Duchesne

Jasmin

2022

The Journal of Physiology

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“…Therefore we analyzed if RSV as a caloric restriction mimetic affected alternative splicing. The effect of RSV on alternative splicing is limited, but it has been reported to affect a few genes including: the insulin receptor gene (INSR), the survival motor neuron gene 2 (SMN2), and the serine/arginine-rich splicing factor 3 (SRSF3) [65][66][67].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

Dembić

Andersen

Bastin

et al. 2019

Molecular Genetics and Metabolism

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Resveratrol (RSV) is a small compound first identified as an activator of sirtuin 1 (SIRT1), a key factor in mediating the effects of caloric restriction. Since then, RSV received great attention for its widespread beneficial effects on health and in connection to many diseases. RSV improves the metabolism and the mitochondrial function, and more recently it was shown to restore fatty acid βoxidation (FAO) capacities in patient fibroblasts harboring mutations with residual enzyme activity. Many of RSV's beneficial effects are mediated by the transcriptional coactivator PGC-1α, a direct target of SIRT1 and a master regulator of the mitochondrial fatty acid oxidation. Despite numerous studies RSV's mechanism of action is still not completely elucidated. Our aim was to investigate the effects of RSV on gene regulation on a wide scale, possibly to detect novel genes whose upregulation by RSV may be of interest with respect to disease treatment. We performed Next Generation Sequencing of RNA on normal fibroblasts treated with RSV. To investigate whether the effects of RSV are mediated through SIRT1 we expanded the analysis to include SIRT1knockdown fibroblasts. We identified the aspartoacylase (ASPA) gene, mutated in Canavan disease, to be strongly up-regulated by RSV in several cell lines, including Canavan disease fibroblasts. We further link RSV to the up-regulation of other genes involved in myelination including the glial specific transcription factors POU3F1, POU3F2, and myelin basic protein (MBP). We also observe a strong up-regulation by RSV of the riboflavin transporter gene SLC52a1. Mutations in SLC52a1 cause transient multiple acyl-CoA dehydrogenase deficiency (MADD). Our analysis of alternative splicing identified novel metabolically important genes affected by RSV, among which is particularly interesting the α subunit of the stimulatory G protein (Gsα), which regulates the cellular levels of cAMP through adenylyl cyclase. We conclude that in fibroblasts RSV stimulates the PGC-1α and p53 pathways, and up-regulates genes affecting the glucose metabolism, mitochondrial β-oxidation, and mitochondrial biogenesis. We further confirm that RSV might be a relevant treatment in the correction of FAO deficiencies and we suggest that treatment in other metabolic disorders including Canavan disease and MADD might be also beneficial.

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“…Although other pathophysiological mechanisms could be involved in the development of insulin resistance in DM1, toxic aberrant mRNA resulting in dysregulated splicing of the insulin receptor mRNA is currently best supported in the literature. Of note, dysregulated IR splicing in muscle could provide a therapeutic target in DM1, as has been hinted at in a recent study (151).…”

Section: Molecular Evidence Of Insulin Signaling Involvement In Dm1mentioning

confidence: 78%

Insulin Signaling as a Key Moderator in Myotonic Dystrophy Type 1

et al. 2019

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Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease characterized by multi-system involvement. Affected organ system includes skeletal muscle, heart, gastro-intestinal system and the brain. In this review, we evaluate the evidence for alterations in insulin signaling and their relation to clinical DM1 features. We start by summarizing the molecular pathophysiology of DM1. Next, an overview of normal insulin signaling physiology is given, and evidence for alterations herein in DM1 is presented. Clinically, evidence for involvement of insulin signaling pathways in DM1 is based on the increased incidence of insulin resistance seen in clinical practice and recent trial evidence of beneficial effects of metformin on muscle function. Indirectly, further support may be derived from certain CNS derived symptoms characteristic of DM1, such as obsessive-compulsive behavior features, for which links with altered insulin signaling has been demonstrated in other diseases. At the basic scientific level, several pathophysiological mechanisms that operate in DM1 may compromise normal insulin signaling physiology. The evidence presented here reflects the importance of insulin signaling in relation to clinical features of DM1 and justifies further basic scientific and clinical, therapeutically oriented research.

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Resveratrol enhances splicing of insulin receptor exon 11 in myotonic dystrophy type 1 fibroblasts

Cited by 12 publications

References 36 publications

Pharmacological and exercise‐induced activation of AMPK as emerging therapies for myotonic dystrophy type 1 patients

Pharmacological and exercise‐induced activation of AMPK as emerging therapies for myotonic dystrophy type 1 patients

Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

Insulin Signaling as a Key Moderator in Myotonic Dystrophy Type 1

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