Constantin Despina, Constantin-Teodosiu Dumitru, Layfield Robert, Tsintzas Kostas, Bennett Andrew J, Greenhaff Paul L
Centre for Integrated Systems Biology and Medicine, Queens Medical Centre, University of Nottingham Medical School, Nottingham NG7 2UH, UK.
J Physiol. 2007 Aug 15;583(Pt 1):381-90. doi: 10.1113/jphysiol.2007.135459. Epub 2007 May 31.
PPARalpha agonism impairs mitochondrial function, but the effect of PPARdelta agonism on mitochondrial function is equivocal. Furthermore, PPARalpha and delta agonism increases muscle fatty acid oxidation, potentially via activation of FOXO1 signalling and PDK4 transcription. Since FOXO1 activation has also been suggested to increase transcription of MAFbx and MuRF-1, and thereby the activation of ubiquitin-proteasome mediated muscle proteolysis, this raises the possibility that muscle fuel selection and the induction of a muscle atrophy programme could be regulated by a single common signalling pathway. We therefore investigated the effect of PPARdelta (delta) agonist, GW610742, administration on muscle mitochondrial function, fuel regulation, and atrophy and growth related signalling pathways in vivo. Twenty-four male Wistar rats received vehicle or GW610742 (5 and 100 mg per kg body mass (bm)) orally for 6 days. Soleus muscle was used to determine maximal rates of ATP production (MRATP) in isolated mitochondria, gene and protein expression, and enzyme activities. MRATP were unchanged by GW610742. Muscle PDK2 and PDK4 mRNA expression increased with GW610742 (100 mg (kg bm)(-1)) compared to vehicle (P<0.05), and was paralleled by a twofold increase in PDK4 protein expression (P<0.05). The activity of beta-hydroxyacyl-CoA dehydrogenase increased with GW610742 (P<0.05). Muscle MuRF1 and MAFbx mRNA expression was increased by GW610742 (100 mg (kg bm)(-1)) compared to vehicle (P<0.05), and was matched by increased protein expression (P<0.001), whilst Akt1 protein declined (P<0.05). There was no effect of GW610742 on 20S proteasome activity and mRNA expression, or the muscle DNA: protein ratio. GW610742 switched muscle fuel metabolism towards decreased carbohydrate use and enhanced lipid utilization, but did not induce mitochondrial dysfunction. Furthermore, GW610742 initiated a muscle atrophy programme, possibly via changes in the Akt1/FOXO/MAFbx and MuRF1 signalling pathway.
过氧化物酶体增殖物激活受体α（PPARα）激动作用会损害线粒体功能，但PPARδ激动作用对线粒体功能的影响尚不明确。此外，PPARα和δ激动作用会增加肌肉脂肪酸氧化，这可能是通过激活FOXO1信号传导和PDK4转录来实现的。由于也有人提出FOXO1激活会增加MAFbx和MuRF-1的转录，从而激活泛素-蛋白酶体介导的肌肉蛋白水解，这就增加了一种可能性，即肌肉燃料选择和肌肉萎缩程序的诱导可能受单一共同信号通路调控。因此，我们研究了PPARδ（δ）激动剂GW610742在体内对肌肉线粒体功能、燃料调节以及萎缩和生长相关信号通路的影响。24只雄性Wistar大鼠口服给予溶剂或GW610742（每千克体重5毫克和100毫克），持续6天。使用比目鱼肌来测定分离线粒体中ATP产生的最大速率（MRATP）、基因和蛋白质表达以及酶活性。GW610742对MRATP没有影响。与溶剂相比，GW610742（100毫克/（千克体重）⁻¹）使肌肉PDK2和PDK4 mRNA表达增加（P<0.05），同时PDK4蛋白表达增加了两倍（P<0.05）。β-羟酰基辅酶A脱氢酶的活性随GW610742增加（P<0.05）。与溶剂相比，GW610742（100毫克/（千克体重）⁻¹）使肌肉MuRF1和MAFbx mRNA表达增加（P<0.05），且蛋白质表达也相应增加（P<0.001），而Akt1蛋白减少（P<0.05）。GW610742对20S蛋白酶体活性和mRNA表达或肌肉DNA与蛋白质的比例没有影响。GW610742使肌肉燃料代谢转向减少碳水化合物利用并增强脂质利用，但未诱导线粒体功能障碍。此外，GW610742可能通过Akt1/FOXO/MAFbx和MuRF1信号通路的变化启动了肌肉萎缩程序。
