A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance

Liu, Yuan; Jurczak, Michael J.; Lin, Bo; Larsen, Mads; Kennerdell, Jason R.; Chen, Yanwen; Huckestein, Brydie R.; Nguyen, Matthew K.; Tuncer, Ferhan; Jiang, Yu; Monga, Satdarshan P.; O’Donnell, Christopher P.; Finkel, Toren; Chen, Bill B.; Mallampalli, Rama K.

doi:10.1038/s41589-020-00723-0

Cited by 18 publications

(15 citation statements)

References 57 publications

(56 reference statements)

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“…Across the different gene sets identified in this study, several of the genes with the lowest p-values (SLC39A8, IRS2, FBXO48) and one WikiPathway (transcription factor regulation in adipogenesis) were associated with insulin signaling or more broadly related to metabolism/ adipogenesis [61][62][63]. Dysregulation of insulin signaling has been linked to clinical features of DM1 and is an actively ongoing field of investigation [64].…”

Section: Discussionmentioning

confidence: 86%

Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood

Cruchten

As²,

Glennon³

et al. 2022

BMC Med

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Background Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Through a process of reverse engineering, this study aims to identify druggable molecular biomarkers associated with the clinical improvement in the OPTIMISTIC cohort. Methods Based on full blood samples collected during OPTIMISTIC, we performed paired mRNA sequencing for 27 patients before and after the CBT intervention. Linear mixed effect models were used to identify biomarkers associated with the disease-causing CTG expansion and the mean clinical improvement across all clinical outcome measures. Results We identified 608 genes for which their expression was significantly associated with the CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes associated with both returned to more normal levels in patients who benefited the most from CBT. This main finding has been replicated based on an external dataset of mRNA data of DM1 patients and controls, singling these genes out as candidate biomarkers for therapy response. Among these candidate genes were DNAJB12, HDAC5, and TRIM8, each belonging to a protein family that is being studied in the context of neurological disorders or muscular dystrophies. Across the different gene sets, gene pathway enrichment analysis revealed disease-relevant impaired signaling in, among others, insulin-, metabolism-, and immune-related pathways. Furthermore, evidence for shared dysregulations with another neuromuscular disease, Duchenne muscular dystrophy, was found, suggesting a partial overlap in blood-based gene dysregulation. Conclusions DM1-relevant disease signatures can be identified on a molecular level in peripheral blood, opening new avenues for drug discovery and therapy efficacy assessments.

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Section: Discussionmentioning

confidence: 86%

Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood

Cruchten

As²,

Glennon³

et al. 2022

BMC Med

View full text Add to dashboard Cite

show abstract

“…Across the different gene sets identified in this study several of the most significant genes ( SLC39A8, IRS2, FBXO48) and one WikiPathway (Transcription factor regulation in adipogenesis) were associated with insulin signaling or more broadly related to metabolism/adipogenesis [54–56]. Dysregulation of insulin signaling has been associated with clinical features of DM1 and is an actively ongoing field of investigation [57].…”

Section: Discussionmentioning

confidence: 99%

Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood

Cruchten

Glennon

et al. 2022

Preprint

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Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Here, we performed mRNA sequencing of full blood for 27 patients of the OPTIMISTIC cohort before and after the CBT intervention. We identified 608 genes for which their expression was significantly associated with the disease causing CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes significantly associated with both returned to more normal levels in patients who benefited most from CBT. This trend was consistent with the difference observed between DM1 patients and controls in an earlier study of blood mRNA expression levels, singling these genes out as candidate biomarkers for therapy response. Together these results highlight the ability to find disease relevant information in full blood of DM1 patients, opening new avenues to monitor therapy effects.

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“…Taken together, these findings indicate that autophagy in podocytes may represent a promising target in DN and other glomerulopathies. Of interest, a highly effective oral inhibitor of activated AMPK degradation has been recently developed [ 237 ] and will be tested in humans. However, given the high degree of complexity of autophagy, fine-tuning of podocyte autophagy is required to achieve clinical benefit.…”

Section: Mechanisms Of Podocyte Injurymentioning

confidence: 99%

Mechanisms of podocyte injury and implications for diabetic nephropathy

2022

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Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.

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A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance

Cited by 18 publications

References 57 publications

Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood

Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood

Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood

Mechanisms of podocyte injury and implications for diabetic nephropathy

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