RGD Reference Report - Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes. - Rat Genome Database

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Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes.

Authors: Roy Chowdhury, SK  Smith, DR  Saleh, A  Schapansky, J  Marquez, A  Gomes, S  Akude, E  Morrow, D  Calcutt, NA  Fernyhough, P 
Citation: Roy Chowdhury SK, etal., Brain. 2012 Jun;135(Pt 6):1751-66. doi: 10.1093/brain/aws097. Epub 2012 May 4.
RGD ID: 7242175
Pubmed: PMID:22561641   (View Abstract at PubMed)
PMCID: PMC3359752   (View Article at PubMed Central)
DOI: DOI:10.1093/brain/aws097   (Journal Full-text)

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 gamma coactivator-1alpha (PGC-1alpha) 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-1alpha is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1alpha 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-1alpha 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-1alpha pathway.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Diabetes Mellitus  ISOPpargc1a (Mus musculus)7242175; 7242175protein:decreased expression:dorsal root ganglia (mouse)RGD 
Experimental Diabetes Mellitus  IEP 7242175protein:decreased expression:dorsal root ganglia (mouse)RGD 
type 2 diabetes mellitus  ISOPpargc1a (Mus musculus)7242175; 7242175protein:decreased expression:dorsal root gangliaRGD 
type 2 diabetes mellitus  IEP 7242175protein:decreased expression:dorsal root ganglia (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ppargc1a  (PPARG coactivator 1 alpha)

Genes (Mus musculus)
Ppargc1a  (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha)

Genes (Homo sapiens)
PPARGC1A  (PPARG coactivator 1 alpha)


Additional Information