The LKB1‐AMPK and mTORC1 Metabolic Signaling Networks in Schwann Cells Control Axon Integrity and Myelination

Beirowski, Bogdan

doi:10.1002/bies.201800075

Cited by 30 publications

(32 citation statements)

References 111 publications

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“…The AMPK/ PGC1α pathway is regulated by many upstream signalling molecular. Several lines of evidence support the involvement of AMPK in mediating the beneficial effects of GLP-1 or GLP-1R 9,44,47,48. Ourresults demonstrated that sitagliptin could activate AMPK/PGC1α pathway.…”

supporting

confidence: 74%

Sitagliptin improves functional recovery via GLP‐1R‐induced anti‐apoptosis and facilitation of axonal regeneration after spinal cord injury

Han

Cheng

et al. 2020

J Cellular Molecular Medi

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Axon growth and neuronal apoptosis are considered to be crucial therapeutic targets against spinal cord injury (SCI). Growing evidences have reported stimulation of glucagon‐like peptide‐1 (GLP‐1)/GLP‐1 receptor (GLP‐1R) signalling axis provides neuroprotection in experimental models of neurodegeneration disease. Endogenous GLP‐1 is rapidly degraded by dipeptidyl peptidase‐IV (DPP4), resulting in blocking of GLP‐1/GLP1R signalling process. Sitagliptin, a highly selective inhibitor of DPP4, has approved to have beneficial effects on diseases in which neurons damaged. However, the roles and the underlying mechanisms of sitagliptin in SCI repairing remain unclear. In this study, we used a rat model of SCI and PC12 cells/primary cortical neurons to explore the mechanism of sitagliptin underlying SCI recovery. We discovered the expression of GLP‐1R decreased in the SCI model. Administration of sitagliptin significantly increased GLP‐1R protein level, alleviated neuronal apoptosis, enhanced axon regeneration and improved functional recovery following SCI. Nevertheless, treatment with exendin9‐39, a GLP‐1R inhibitor, remarkably reversed the protective effect of sitagliptin. Additionally, we detected the AMPK/PGC‐1α signalling pathway was activated by sitagliptin stimulating GLP‐1R. Taken together, sitagliptin may be a potential agent for axon regrowth and locomotor functional repair via GLP‐1R‐induced AMPK/ PGC‐1α signalling pathway after SCI.

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supporting

confidence: 74%

Sitagliptin improves functional recovery via GLP‐1R‐induced anti‐apoptosis and facilitation of axonal regeneration after spinal cord injury

Han

Cheng

et al. 2020

J Cellular Molecular Medi

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“…While not all reductions reached statistical significance, the combined effect of decreasing several could significantly reduce astrocyte glucose uptake and glycogen synthesis, reduce lactate production, and reduce lactate export through MCT1. This is consistent with findings that LKB1 depletion from SC reduced lactate release (Beirowski, 2019), and in drosophila, LKB1 increases lactate transporter trafficking (Jang, Lee, & Chung, 2008). While the importance of lactate transfer from astrocytes to neurons to neuronal function and survival remains controversial (Magistretti & Allaman, 2018;Pellerin & Magistretti, 2012), evidence exists that in inactive MS lesions, a shift to increased glycolysis increases lactate shuttling between astrocytes and neurons, thought to be critical for the survival of demyelinated axons (Nijland et al, 2015).…”

Section: Astrocyte Metabolic Dysfunction Contribution To Disease Sesupporting

confidence: 85%

Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis

Kalinin

Meares

Lin

et al. 2019

Glia

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Liver kinase B1 (LKB1) is a ubiquitously expressed kinase involved in the regulation of cell metabolism, growth, and inflammatory activation. We previously reported that a single nucleotide polymorphism in the gene encoding LKB1 is a risk factor for multiple sclerosis (MS). Since astrocyte activation and metabolic function have important roles in regulating neuroinflammation and neuropathology, we examined the serine/threonine kinase LKB1 in astrocytes in a chronic experimental autoimmune encephalomyelitis mouse model of MS. To reduce LKB1, a heterozygous astrocyte-selective conditional knockout (het-cKO) model was used. While disease incidence was similar, disease severity was worsened in het-cKO mice. RNAseq analysis identified Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched in het-cKO mice relating to mitochondrial function, confirmed by alterations in mitochondrial complex proteins and reductions in mRNAs related to astrocyte metabolism. Enriched pathways included major histocompatibility class II genes, confirmed by increases in MHCII protein in spinal cord and cerebellum of het-cKO mice. We observed increased numbers of CD4+ Th17 cells and increased neuronal damage in spinal cords of het-cKO mice, associated with reduced expression of choline

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“…48 Others found that upregulating AMPK signaling-induced SCs proliferation and migration. 49,50 In this study, our loss-of-function study in AMPK signaling indicated that AMPK signaling had an important effect on SC proliferation and migration.…”

Section: Discussionmentioning

confidence: 69%

ANXA1 directs Schwann cells proliferation and migration to accelerate nerve regeneration through the FPR2/AMPK pathway

et al. 2020

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Many factors are involved in the process of nerve regeneration. Understanding the mechanisms regarding how these factors promote an efficient remyelination is crucial to deciphering the molecular and cellular processes required to promote nerve repair. Schwann cells (SCs) play a central role in the process of peripheral nerve repair/regeneration. Using a model of facial nerve crush injury and repair, we identified Annexin A1 (ANXA1) as the extracellular trigger of SC proliferation and migration. ANXA1 activated formyl peptide receptor 2 (FPR2) receptors and the downstream adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK) signaling cascade, leading to SC proliferation and migration in vitro. SCs lacking FPR2 or AMPK displayed a defect in proliferation and migration. After facial nerve injury (FNI), ANXA1 promoted the proliferation of SCs and nerve regeneration in vivo. Collectively, these data identified the ANXA1/FPR2/AMPK axis as an important pathway in SC proliferation and migration. ANXA1‐induced remyelination and SC proliferation promotes FNI regeneration.

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The LKB1‐AMPK and mTORC1 Metabolic Signaling Networks in Schwann Cells Control Axon Integrity and Myelination

Cited by 30 publications

References 111 publications

Sitagliptin improves functional recovery via GLP‐1R‐induced anti‐apoptosis and facilitation of axonal regeneration after spinal cord injury

Sitagliptin improves functional recovery via GLP‐1R‐induced anti‐apoptosis and facilitation of axonal regeneration after spinal cord injury

Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis

ANXA1 directs Schwann cells proliferation and migration to accelerate nerve regeneration through the FPR2/AMPK pathway

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