Abstract
Aims/hypothesisDissipating energy via mitochondrial uncoupling has been suggested to contribute to enhanced insulin sensitivity. We hypothesised that skeletal muscle mitochondria of endurance-trained athletes have increased sensitivity for fatty acid (FA)-induced uncoupling, which is driven by the mitochondrial protein adenine nucleotide translocase 1 (ANT1).MethodsCapacity for FA-induced uncoupling was measured in endurance-trained male athletes (T) and sedentary young men (UT) in an observational study and also in isolated skeletal muscle mitochondria from Zucker diabetic fatty (ZDF) rats and C2C12 myotubes following small interfering RNA (siRNA)-mediated gene silencing of ANT1. Thus, fuelled by glutamate/succinate (fibres) or pyruvate (mitochondria and myotubes) and in the presence of oligomycin to block ATP synthesis, increasing levels of oleate (fibres) or palmitate (mitochondria and myotubes) were automatically titrated while respiration was monitored. Insulin sensitivity was measured by hyperinsulinaemic–euglycaemic clamp in humans and via insulin-stimulated glucose uptake in myotubes.ResultsSkeletal muscle from the T group displayed increased sensitivity to FA-induced uncoupling (p = 0.011) compared with muscle from the UT group, and this was associated with elevated insulin sensitivity (p = 0.034). ANT1 expression was increased in T (p = 0.013). Mitochondria from ZDF rats displayed decreased sensitivity for FA-induced uncoupling (p = 0.008). This difference disappeared in the presence of the adenine nucleotide translocator inhibitor carboxyatractyloside. Partial knockdown of ANT1 in C2C12 myotubes decreased sensitivity to the FA-induced uncoupling (p = 0.008) and insulin-stimulated glucose uptake (p = 0.025) compared with controls.Conclusions/interpretationIncreased sensitivity to FA-induced uncoupling is associated with enhanced insulin sensitivity and is affected by ANT1 activity in skeletal muscle. FA-induced mitochondrial uncoupling may help to preserve insulin sensitivity in the face of a high supply of FAs.Trial registrationwww.trialregister.nl NTR2002
Highlights
Endurance exercise training has beneficial effects on mitochondrial oxidative capacity in skeletal muscle and is associated with enhanced muscle insulin sensitivity
To further study the role of adenine nucleotide translocase 1 (ANT1) in fatty acid (FA)-induced uncoupling in relation to insulin responsiveness, we examined isolated skeletal muscle mitochondria obtained from a rodent model of type 2 diabetes (Zucker diabetic fatty [ZDF] rats) and employed a small interfering RNA-mediated gene silencing of Ant1 in C2C12 myotubes
Insulin sensitivity and FA-induced uncoupling in T and UT We determined FA-induced uncoupling in skeletal muscle fibres from nine T and ten UT, in whom we previously reported higher insulin sensitivity and reduced lipid-induced insulin resistance in T compared with UT [4]
Summary
Endurance exercise training has beneficial effects on mitochondrial oxidative capacity in skeletal muscle and is associated with enhanced muscle insulin sensitivity. Using in vivo MR spectroscopy, a 54% higher basal rate of substrate oxidation through the tricarboxylic acid (TCA) cycle was observed in athletes compared with matched sedentary controls [5]. Despite this increased basal TCA cycle flux, ATP synthesis rates were similar, indicating a decrease in the efficiency of mitochondrial coupling. The study [5] concluded that increased mitochondrial uncoupling may represent an additional mechanism by which endurance exercise training enhances muscle insulin sensitivity; in accordance, muscle-specific overexpression of uncoupling protein (UCP) 1 [6] and UCP3 [7] in rodents protect against lipid-induced insulin resistance
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