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
Submitted By Nigel Calcutt on 1/30/2013
Status Published
Journal Brain : a journal of neurology
Year 2012
Date Published 6/1/2012
Volume : Pages 135 : 1751 - 1766
PubMed Reference 22561641
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 ? coactivator-1a (PGC-1a) 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-1a is decreased under
hyperglycaemia. In this study, we tested the hypothesis that deficits in
adenosine monophosphate-activated protein kinase/PGC-1a 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-1a 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-1a pathway.

Investigators with authorship
Nigel CalcuttUniversity of California San Diego