Lemieux 2013 Abstract MiP2013

From Bioblast
Lemieux H, Warren BE, Lucchinetti E, Lou PH, Zhang L, Gandhi M, Clanachan AS, Zaugg M(2013) Early mitochondrial dysfunction associated with type 2 diabetes mellitus in the heart and skeletal muscle. Mitochondr Physiol Network 18.08.

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Helene Lemieux

MiP2013, Book of Abstracts Open Access

Lemieux H, Warren BE, Lucchinetti E, Lou PH, Zhang L, Gandhi M, Clanachan AS, Zaugg M (2013)

Event: MiPNet18.08_MiP2013

As a consequence of the rising overall obesity and aging of the population, insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are becoming more prevalent in developing countries. Although evidence has been accumulating that T2DM is accompanied by mitochondrial dysfunction in muscles, the link between the mitochondrial dysfunction and the pathogenesis of T2DM remains unclear [1]. T2DM is a complex disease that causes various changes in the body metabolism. The difficulty is to identify mitochondrial defects involved in the cause of the disease rather than those that occur as consequences of the disease. Our study aims at understanding the role of mitochondrial metabolism in the muscle during the early stages of T2DM.

The fructose-fed rat was used as the animal model of pre-diabetes. After only 6 weeks of a fructose-enriched diet (10% fructose added to the drinking water), rats showed clear signs of IR (glucose tolerance test). Mitochondrial respiration was measured in permeabilized muscle fibers using high-resolution respirometry (Oroboros Instruments, Austria) in the cardiac muscle and in two skeletal muscles, one oxidative (soleus) and one glycolytic (extensor digitorum longus, EDL). A wide range of substrates were used in order to cover the carbohydrate metabolism and the fatty acid oxidation. Acylcarnitine profiles were also measured in each tissue.

The mitochondrial content was preserved in skeletal muscle as shown by the lack of difference of citrate synthase (CS) activity and Complex IV respiration. In the heart, CS activity was slightly, but significantly, reduced in the fructose-fed rats. The soleus muscle shows a decrease in Complex II respiration (succinate+rotenone) whereas the EDL muscle shows reduced Complex I and CI+II respiration in the presence of pyruvate but not when glutamate is used as a substrate. There is no defect in fatty acid oxidation with the soleus muscle in fructose-fed animals. The EDL muscle, however, shows a defect located in the long-chain acyl-CoA dehydrogenase (LCAD). Surprisingly, the mitochondrial dysfunction in the heart mirrors the mitochondrial dysfunction in the EDL muscle, rather than in the soleus.

Our results highlight important early mitochondrial dysfunction associated with T2DM. The defects are clearly specific to the type of muscle studied. Furthermore, our study also points to the importance of differences between human and animal models because the role of LCAD in fatty acid oxidation is significant in rodent muscles but not in most human tissues [2].


β€’ O2k-Network Lab: CA Edmonton Lemieux H, CA Edmonton Zaugg M


Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Comparative MiP;environmental MiP, Exercise physiology;nutrition;life style, mt-Medicine  Pathology: Diabetes 

Organism: Rat  Tissue;cell: Heart, Skeletal muscle  Preparation: Permeabilized tissue  Enzyme: Marker enzyme 

Coupling state: OXPHOS  Pathway: F, N, S, CIV, NS, Other combinations  HRR: Oxygraph-2k 

MiP2013 


Affiliations and author contributions

1 - Campus Saint-Jean, University of Alberta, Edmonton, Canada; 2 - Dept of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Canada; 3 - Dept of Pharmacology, University of Alberta, Edmonton, Canada.

Email: hlne@ualberta.ca

References

  1. Brands M, Verhoeven AJ, Serlie MJ (2012) Role of mitochondrial function in insulin resistance. Adv Exp Med Biol 942: 215-234.
  2. Chegary M, Brinke HT, Ruiter JP, Wijburg FA, Stoll MS, Minkler PE, van Weeghel M, Schulz H, Hoppel CL, Wanders RJ, Houten SM (2009) Mitochondrial long chain fatty acid beta-oxidation in man and mouse. Biochim Biophys Acta 1791: 806-815.


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