Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes.
Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic dema...
| Publicado en: | Brain: A Journal of Neurology Vol. 135; no. 6; pp. 1751 - 1767 |
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| Autores principales: | , , , , , , , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Oxford University Press / USA
Jun2012
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=104450812&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 104450812 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00068950 2RY jtl: Brain: A Journal of Neurology issn: 00068950 maglogo: N pubinfo: dt: Jun2012 vid: 135 iid: 6 pid: 622 pub: Oxford University Press / USA artinfo: ui: 104450812 NLM22561641 2011562058 10.1093/brain/aws097 NLM22561641 PMC3359752 104450812 ppf: 1751 ppct: 16 formats: tig: atl: Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes. aug: au: Roy Chowdhury SK Smith DR Saleh A Schapansky J Marquez A Gomes S Akude E Morrow D Calcutt NA Fernyhough P Roy Chowdhury, Subir K Smith, Darrell R Saleh, Ali Schapansky, Jason Marquez, Alexandra Gomes, Suzanne Akude, Eli Morrow, Dwane Calcutt, Nigel A Fernyhough, Paul affil: Division of Neurodegenerative Disorders, St. Boniface Hospital Research Centre, R4023-1 - 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada sug: subj: Ganglia, Sensory Pathology Mitochondrial Diseases Pathology Peripheral Nervous System Diseases Pathology Phosphotransferases Metabolism Sensory Receptor Cells Signal Transduction Physiology Adenosine Triphosphate Pharmacodynamics Analysis of Variance Animal Studies Antiinflammatory Agents, Non-Steroidal Therapeutic Use Blood Glucose Drug Effects Body Weight Drug Effects Cell Membrane Drug Effects Cells Cytological Techniques Diabetes Mellitus Complications Dose-Response Relationship, Drug Genes Drug Effects Genetics Hyperalgesia Physiopathology Male Membrane Potentials Mice Mitochondrial Diseases Drug Therapy Mitochondrial Diseases Etiology Models, Biological Mutation Nerve Fibers Pathology Neurons Pathology Oxygen Consumption Drug Effects Peripheral Nervous System Diseases Drug Therapy Peripheral Nervous System Diseases Etiology Physical Stimulation Adverse Effects Proteins Proteins Metabolism Rats Reaction Time Reaction Time Drug Effects Sensory Receptor Cells Drug Effects Sensory Receptor Cells Pathology Signal Transduction Drug Effects Stilbenes Therapeutic Use Male ab: Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3-5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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