Constantin-Teodosiu Dumitru, Baker David J, Constantin Despina, Greenhaff Paul L
Centre for Integrated Systems Biology and Medicine, Queens Medical Centre, University of Nottingham Medical School, Nottingham NG7 2UH, UK.
J Physiol. 2009 Jan 15;587(1):231-9. doi: 10.1113/jphysiol.2008.164210. Epub 2008 Nov 10.
We have recently shown that PPARdelta agonism, used clinically to treat insulin resistance, increases fat oxidation and up-regulates mitochondrial PDK4 mRNA and protein expression in resting skeletal muscle. We hypothesized that PDK4 up-regulation, which inhibits pyruvate dehydrogenase complex (PDC)-dependent carbohydrate (CHO) oxidation, would negatively affect muscle function during sustained contraction where the demand on CHO is markedly increased. Three groups of eight male Wistar rats each received either vehicle or a PPARdelta agonist (GW610742X) at two doses (5 and 100 mg (kg body mass (bm))(-1) orally for 6 days. On the seventh day, the gastrocnemius-soleus-plantaris muscle group was isolated and snap frozen, or underwent 30 min of electrically evoked submaximal intensity isometric contraction using a perfused hindlimb model. During contraction, the rate of muscle PDC activation was significantly lower at 100 mg (kg bm)(-1) compared with control (P < 0.01). Furthermore, the rates of muscle PCr hydrolysis and lactate accumulation were significantly increased at 100 mg (kg bm)(-1) compared with control, reflecting lower mitochondrial ATP generation. Muscle tension development during contraction was significantly lower at 100 mg (kg bm)(-1) compared with control (25%; P < 0.05). The present data demonstrate that PPARdelta agonism inhibits muscle CHO oxidation at the level of PDC during prolonged contraction, and is paralleled by the activation of anaerobic metabolism, which collectively impair contractile function.
我们最近发现，临床上用于治疗胰岛素抵抗的PPARδ激动剂可增加脂肪氧化，并上调静息骨骼肌中线粒体PDK4 mRNA和蛋白的表达。我们推测，抑制丙酮酸脱氢酶复合体（PDC）依赖性碳水化合物（CHO）氧化的PDK4上调，会在持续收缩期间对肌肉功能产生负面影响，因为此时对CHO的需求会显著增加。三组雄性Wistar大鼠，每组8只，分别接受溶剂对照或两种剂量（5和100 mg·(kg体重(bm))⁻¹）的PPARδ激动剂（GW610742X），口服给药6天。在第7天，分离腓肠肌-比目鱼肌-跖肌肌群并速冻，或使用灌注后肢模型进行30分钟的电诱发次最大强度等长收缩。在收缩过程中，与对照组相比，100 mg·(kg体重(bm))⁻¹剂量组的肌肉PDC激活率显著降低（P < 0.01）。此外，与对照组相比，100 mg·(kg体重(bm))⁻¹剂量组的肌肉磷酸肌酸（PCr）水解率和乳酸积累率显著增加，这反映出线粒体ATP生成减少。与对照组相比，100 mg·(kg体重(bm))⁻¹剂量组在收缩期间的肌肉张力发展显著降低（25%；P < 0.05）。目前的数据表明，PPARδ激动作用在长时间收缩期间在PDC水平抑制肌肉CHO氧化，同时伴有无氧代谢的激活，这共同损害了收缩功能。
