Diet-induced modulation of mitochondrial activity in rat muscle

Abstract

Growing evidence supports the theory that mitochondrial dysfunction is an underlying cause of intramyocellular lipid (IMCL) accumulation and insulin resistance. Here, we hypothesized that high dietary fat (HF) intake could trigger changes in mitochondrial activity such that fatty acid oxidation is impaired in muscle and contributes to an elevation in intramyocellular lipid (IMCL) levels. Muscle mitochondrial activity was determined in vivo through measurement of the F1F0 ATP synthase flux, the terminal step in the oxidative phosphorylation process. An initial study comparing rats on normal chow diet with rats on an HF diet revealed strong correlations between muscle ATP synthesis rates, IMCL levels and whole body glucose tolerance. Results obtained from two latter studies showed multiphasic responses to dietary intervention. Initially, the ATP synthesis rates decreased as much as 50% within 24 h of raising the fat content in the diet to 60% of the caloric intake. These rates eventually returned to normal values after 2-3 wk on the HF regimen, seemingly to prevent further IMCL accumulation. Only beyond 1 mo on the HF diet did results consistently show ATP synthesis rates to diminish by 30 -50% accompanied by steadily augmenting IMCL levels. Interestingly, switching back to a chow diet after 3 wk of HF feeding reversed the initial diet-induced changes. Although the muscle mitochondrial system may initially offer enough compliance to counteract lipid surplus, these in vivo data suggest a vicious long-term cycle among mitochondrial dysfunction, IMCL accumulation, and glucose intolerance in the rat. 31 P nuclear magnetic resonance spectroscopy; intramyocellular lipids; adenosine triphosphate synthesis; skeletal muscle; insulin resistance

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

“…The duration of high-fat feeding also seems to differently affect mitochondrial function in skeletal muscle. In fact, oxidative phosphorylation was found increased after short-term (2-3 weeks) dietary treatment, but decreased after long-term treatment (Chanseaume et al 2007, Laurent et al 2007, Bonnard et al 2008). …”

Free fatty acids and skeletal muscle insulin resistance

“…For example it has been reported that a high dietary fat intake can downregulate oxidative gene expression in muscle of humans and rodents [32], whereas more recent studies found that fat feeding increased fatty acid oxidation enzymes and mitochondrial fatty acid oxidative capacity [33 ,34 ]. Other reports do suggest changes in ATP production rates [35] and mitochondrial function after prolonged fat feeding [36 ] but not at the early time points (2-5 weeks) when muscle insulin resistance is already clearly evident in fat-fed rodents [1,37]. Thus it seems likely that there is an initial upregulation of both fatty acid clearance into muscle, and the subsequent ability to oxidize the fatty acids in insulin-resistant rodents, although presumably the latter is insufficient to prevent cytosolic lipid accumulation in the presence of a high fatty acid supply to muscle.…”

Evaluation of in vivo mitochondrial bioenergetics in skeletal muscle using NMR and optical methods

“…However, the contributions of flux through the glycolytic enzymes GAPDH and PGK have been clearly demonstrated[58–60]. These reactions are near equilibrium and thus large unidirectional fluxes far exceed flux through the F 1 F O ATPase and significantly contribute to the ST measurements without contributing to the net ATP synthesis[61]. The contributions from these near equilibrium glycolytic enzymes has been cited to explain the much higher ATP flux measurements from ST compared to those reported using other in vivo approaches[62, 63].…”