title: Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes.
abstract: 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.
authors.affiliation: Division of Neurodegenerative Disorders, St. Boniface Hospital Research Centre, R4023-1 - 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada. srchowdhury@sbrc.ca
authors.forename: Subir K
authors.initials: SK
authors.lastname: Roy Chowdhury
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Smith
authors.forename: Ali
authors.initials: A
authors.lastname: Saleh
authors.forename: Jason
authors.initials: J
authors.lastname: Schapansky
authors.forename: Alexandra
authors.initials: A
authors.lastname: Marquez
authors.forename: Suzanne
authors.initials: S
authors.lastname: Gomes
authors.forename: Eli
authors.initials: E
authors.lastname: Akude
authors.forename: Dwane
authors.initials: D
authors.lastname: Morrow
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Calcutt
authors.forename: Paul
authors.initials: P
authors.lastname: Fernyhough
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D016501:Neurites / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010812:Physical Stimulation / Q000009:adverse effects; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D000077185:Resveratrol; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013267:Stilbenes / Q000627:therapeutic use; D014157:Transcription Factors / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D013267:Stilbenes; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol