Abstract Details

Title Molecular link between insulin resistance and skeletal muscle atrophy in myotonic dystrophies

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P2 - Poster Session 2 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-043

Objective To further investigate the molecular mechanisms that induce insulin resistance in skeletal muscle from myotonic dystrophy type 1 (DM1) and type 2 (DM2) patients and whether these mechanisms may contribute to progressive muscle wasting and weakness.

Background DM1 and DM2 are autosomal dominant neuromuscular disorders characterized by muscle weakness and atrophy, myotonia and insulin resistance. They are caused by nuclear accumulation of mutant RNA containing CUG/CCUG repeats, which lead to missplicing of different genes. The missplicing of insulin receptor and post-receptor insulin signalling abnormalities have been associated with insulin resistance, however the precise molecular defects that cause metabolic dysfunctions are still unclear. In absence of insulin stimulus, atrophy and decrease of strength can be observed thus contributing to progressive DM muscle wasting and weakness.

Design/Methods The response to insulin action was analysed ex vivo on muscle biopsies obtained from 8 DM1, 3 DM2 and 3 healthy subjects (CTR). Three patients affected by motor neuron disease and 3 Type 2 Diabetes Mellitus affected patients were used as internal controls. The phosphorylation of key proteins of IRS-1-Akt/PKB and Ras-ERK insulin pathways were analysed by western blot. Data have been correlated to muscle histological alterations and muscle insulin receptor protein expression.

Results DM muscle exhibits a defective activation of IRS1, ERK1/2, AS160, AKT/PKB and p70S6K after insulin stimulation. These alterations seem to be dependent to a lower expression of the insulin receptor in type 1 fibers in DM patients. The aberrant insulin signalling activation leads to a lower phosphorylation of mTOR and FoxO1 in DM compared to CTR muscle leading to a dysregulation of protein metabolism and explaining muscle fiber atrophy.

Conclusions

Our data indicate that in DM the defective insulin signalling activation can contribute to muscle atrophy, which may be linked to an aberrant specific-fiber type expression of the insulin receptor.

Authors/Disclosures
Giovanni Meola, MD, FAAN PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Barbara Fossati, MD (IRCCS Policlinico San Donato)	No disclosure on file
	No disclosure on file

��ɫ��

��ɫ��