Lemieux 2017 MiP2017
Numerous studies support the effects of diet, age, and type 2 diabetes mellitus (T2DM) on mitochondrial function. However, the sexual dimorphism has received less attention since most of the research is conducted on males. Such bias has limited our comprehension of the role of mitochondria in aging and associated diseases. This study revisits the role of cardiac mitochondrial adjustments during the progression of T2DM, while considering aging and sex as potential confounding factors.
We used Nile rats (NRs) as a T2DM model. In the laboratory, the males but not the females spontaneously develop T2DM with a similar slow progression as occurs in the human; hyperinsulinemia at 2 months, hyperglycemia at 6 months, and metabolic collapse at 18 months . NRs were fed either a standard rodent chow, or a control high-fiber diet (HFiD) established to prevent T2DM  up to 18 months. Mitochondrial content and oxidative phosphorylation (OXPHOS) capacity were assessed in permeabilized fibers from left ventricles at 2, 6, and 18 months. OXPHOS capacity was measured with multiple substrate combinations to assess specific pathways and steps of the electron transport system (ETS) or fatty acid oxidation (FAO). Respiration was expressed as a function of muscle fibers mass, or as Flux control ratio (FCR), relative to the maximal OXPHOS capacity and independent of mitochondrial content.
Mitochondrial content is increased at 2 months in males fed chow compared to HFiD. This early effect is absent in females and does not result in improved mass-specific OXPHOS capacity with any of the substrates. Chow diet also leads to an early increase of FCR for Complex IV in males only. At 6 months, chow diet leads to an increase in mass-specific OXPHOS capacity with substrates investigating the ETS (in male), and the FAO (in both sexes). At 18 months, the only significant effect of diet was an increase in FCR for Complex IV in the females fed the HFiD. Age showed sex- and diet-specific effects on OXPHOS capacity. Only chow-fed males showed a general decrease in mass-specific OXPHOS capacity when feeding electron into the ETS; this is mainly explained by changes in mitochondrial content. Interestingly, only the male fed HFiD show an increase in FCR for Complex IV between 2 and 6 months. The effect of age on FAO showed the same pattern in both sexes, with a decrease in mass-specific capacity in the HFiD animals. In contrast, chow-fed animals of both sexes retain a high FAO capacity over the entire age range.
Our results show clear sexual dimorphism in the variation of OXPHOS capacity with diet and age. Sexual dimorphism essentially affect mitochondrial content and Complex IV relative capacity. Whereas both stimulation of mitochondrial biogenesis and upregulation of Complex IV can occur in response to increases in reactive oxygen species (ROS), such mechanisms have also been suggested to prevent ROS production. The early changes observed in our study are likely related to the development of T2DM in males because these are absent in females, none of which developed T2DM up to 18 months.
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Gender, Exercise physiology;nutrition;life style Pathology: Aging;senescence, Diabetes
Organism: Rat Tissue;cell: Heart Preparation: Permeabilized tissue
Coupling state: OXPHOS Pathway: F, CIV HRR: Oxygraph-2k
- Lemieux H(1), Schneider J(2), Han WH(3), Sauvé Y(2,3)
- Faculty Saint-Jean
- Dept Physiol
- Dept Ophthalmol Vis Sci; Univ Alberta, Canada. – [email protected]
- Yang K, Gotzmann J, Kuny S, Huang H, Sauvé Y, Chan CB (2016) Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes. J Endocrinol 229:343-56.