Mitochondrial energy metabolism in a model of undernutrition induced by dexamethasone

Abstract

The present investigation was undertaken to evaluate whether mitochondrial energy metabolism is altered in a model of malnutrition induced by dexamethasone (DEX) treatment (1·5 mg/kg per d for 5 d). The gastrocnemius and liver mitochondria were isolated from DEX-treated, pair-fed (PF) and control (CON) rats. Body weight was reduced significantly more in the DEX-treated group (2 16 %) than in the PF group (2 9 %). DEX treatment increased liver mass (þ 59 % v. PF, þ23 % v. CON) and decreased gastrocnemius mass. Moreover, in DEX-treated rats, liver mitochondria had an increased rate of non-phosphorylative O 2 consumption with all substrates (approximately þ42 %). There was no difference in enzymatic complex activities in liver mitochondria between rat groups. Collectively, these results suggest an increased proton leak and/or redox slipping in the liver mitochondria of DEX-treated rats. In addition, DEX decreased the thermodynamic coupling and efficiency of oxidative phosphorylation. We therefore suggest that this increase in the proton leak and/or redox slip in the liver is responsible for the decrease in the thermodynamic efficiency of energy conversion. In contrast, none of the variables of energy metabolism determined in gastrocnemius mitochondria was altered by DEX treatment. Therefore, it appears that DEX specifically affects mitochondrial energy metabolism in the liver. Glucocorticoid: Mitochondrion: Oxidative phosphorylation: Respiratory chain complexesMalnutrition is prevalent in many patients, especially in those who are elderly. It causes increased mortality, significant hospital expenditure, reduced muscle and immune function, and decreased quality of life (Wallace et al. 1995;Tucker & Miguel, 1996;Chima et al. 1997;Lesourd & Mazzari, 1997;Landi et al. 2000). Malnutrition results from a negative energy balance, a situation where energy intake fails to meet energy requirements. Although anorexia and a reduced energy intake are always associated with malnutrition, in some clinical circumstances, an increased resting O 2 consumption rate (referred to as increased energy requirements) can be shown (Nguyen et al. 1999). In contrast, most studies with human subjects and animals show that energy restriction decreases energy expenditure (Ramsey et al. 2000). Therefore, it appears that in these clinical states, adaptive mechanisms that lead to a reduction of energy requirements fail to operate. However, the biochemical nature of this negative energy balance phenomenon, i.e. the increased energy expenditure, is poorly understood at the present time. A wasting of energy may be a possible explanation. In other words, the mitochondrial oxidative phosphorylation yield may be less efficient, and in turn O 2 consumption may be increased, for a same ATP synthesis rate.High-dose glucocorticoid treatment affects body weight and body composition (Kochakian & Robertson, 1951;Hausberger & Hausberger, 1958). It has also been found to induce a hypercatabolic state that leads to a reduced muscle mass (Marone et al. 1994;Minet-Q...

Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle

“…In particular, reported prolactin effects on liver and white adipose tissue lipogenic gene expression and function are opposite to those observed after ghrelin treatment in the current study (1). In addition, excess glucocorticoids are not reported to exert independent effects on hepatic lipogenesis and lipid deposition (14,29,54), whereas most (16,18,30), although not all (55), reports agree on their suppressive or null effect on skeletal muscle mitochondrial function. Thus, taken together, the above observations do not support a major role of additional hypophyseal hormonal changes in observed metabolic effects.…”

High Mitochondrial Respiration and Glycolytic Capacity Represent a Metabolic Phenotype of Human Tolerogenic Dendritic Cells

“…1A, 1B). Moreover, it has been described that dexamethasone-treated muscle cells increase the rate of nonphosphorylative oxygen consumption (31) and that vitamin D 3 increases ROS production (32), which may suggest less efficient ATP production from OXPHOS. Interestingly, tolerogenic moDCs were more affected by etomoxir than oligomycin in terms of ATP production.…”

Dexamethasone impairs muscle energetics, studied by 31P NMR, in rats

“…Furthermore, dexamethasone being a highly reproducible model of hypermetabolic stress [12,13,17], a similar experiment was conducted in a parallel group of rats to test plasma substrate and hormone concentrations. In a third experiment, rats were anaesthetised with isoflurane, the skin over the leg was dissected away and the gastrocnemius was rapidly freeze-clamped, removed, frozen in liquid nitrogen and subsequently stored at −80°C until analysis of PCr and creatine concentration.…”

“…GCTC-induced insulin resistance results in decreased insulin-stimulated glucose uptake in muscle [6], and increased plasma concentrations of NEFA, insulin and leptin [7,8], with troglitazone antagonising this effect [7]. At the whole body level, increased GCTC concentrations are known to increase oxygen consumption [9][10][11], and decrease food intake [12,13] resulting in a more negative energy balance than in pair-fed animals. We have shown that there is a decreased efficiency of oxidative phosphorylation in the liver mitochondria of dexamethasone treated rats [13].…”