Malgoyre Alexandra, Chabert Clovis, Tonini Julia, Koulmann Nathalie, Bigard Xavier, Sanchez Hervé
Département des Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France;
Laboratoire de Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier and Institut National de la Santé et de la Recherche Médicale U1055, Grenoble France.
J Appl Physiol (1985). 2017 Mar 1;122(3):666-674. doi: 10.1152/japplphysiol.00090.2016. Epub 2016 Dec 29.
We investigated the effects of chronic hypoxia on the maximal use of and sensitivity of mitochondria to different substrates in rat slow-oxidative (soleus, SOL) and fast-glycolytic (extensor digitorum longus, EDL) muscles. We studied mitochondrial respiration in situ in permeabilized myofibers, using pyruvate, octanoate, palmitoyl-carnitine (PC), or palmitoyl-coenzyme A (PCoA). The hypophagia induced by hypoxia may also alter metabolism. Therefore, we used a group of pair-fed rats (reproducing the same caloric restriction, as observed in hypoxic animals), in addition to the normoxic control fed ad libitum. The resting respiratory exchange ratio decreased after 21 days of exposure to hypobaric hypoxia (simulated elevation of 5,500 m). The respiration supported by pyruvate and octanoate were unaffected. In contrast, the maximal oxidative respiratory rate for PCoA, the transport of which depends on carnitine palmitoyltransferase 1 (CPT-1), decreased in the rapid-glycolytic EDL and increased in the slow-oxidative SOL, although hypoxia improved affinity for this substrate in both muscle types. PC and PCoA were oxidized similarly in normoxic EDL, whereas chronic hypoxia limited transport at the CPT-1 step in this muscle. The effects of hypoxia were mediated by caloric restriction in the SOL and by hypoxia itself in the EDL. We conclude that improvements in mitochondrial affinity for PCoA, a physiological long-chain fatty acid, would facilitate fatty-acid use at rest after chronic hypoxia independently of quantitative alterations of mitochondria. Conversely, decreasing the maximal oxidation of PCoA in fast-glycolytic muscles would limit fatty-acid use during exercise. Affinity for low concentrations of long-chain fatty acids (LCFA) in mitochondria skeletal muscles increases after chronic hypoxia. Combined with a lower respiratory exchange ratio, this suggests facility for fatty acid utilization at rest. This fuel preference is related to caloric restriction in oxidative muscle and to hypoxia in glycolytic one. In contrast, maximal oxidation for LCFA is decreased by chronic hypoxia in glycolytic muscle and can explain glucose dependence at exercise.
我们研究了慢性缺氧对大鼠慢氧化型（比目鱼肌，SOL）和快糖酵解型（趾长伸肌，EDL）肌肉中线粒体对不同底物的最大利用能力及敏感性的影响。我们使用丙酮酸、辛酸、棕榈酰肉碱（PC）或棕榈酰辅酶A（PCoA），在透化的肌纤维中原位研究线粒体呼吸。缺氧引起的摄食减少也可能改变新陈代谢。因此，除了自由摄食的常氧对照组外，我们还使用了一组配对喂养的大鼠（模拟缺氧动物中观察到的相同热量限制）。暴露于低压缺氧（模拟海拔5500米）21天后，静息呼吸交换率降低。丙酮酸和辛酸支持的呼吸不受影响。相反，PCoA的最大氧化呼吸速率在快糖酵解型的EDL中降低，在慢氧化型的SOL中升高，尽管缺氧提高了两种肌肉类型对该底物的亲和力。在常氧的EDL中，PC和PCoA的氧化方式相似，而慢性缺氧限制了该肌肉中CPT-1步骤的转运。缺氧的影响在SOL中由热量限制介导，在EDL中由缺氧本身介导。我们得出结论，线粒体对生理长链脂肪酸PCoA亲和力的提高，将促进慢性缺氧后静息状态下脂肪酸的利用，而与线粒体的数量变化无关。相反，快糖酵解型肌肉中PCoA最大氧化的降低将限制运动期间脂肪酸的利用。慢性缺氧后，线粒体骨骼肌中对低浓度长链脂肪酸（LCFA）的亲和力增加。结合较低的呼吸交换率，这表明静息状态下脂肪酸利用更容易。这种燃料偏好与氧化型肌肉中的热量限制以及糖酵解型肌肉中的缺氧有关。相反，糖酵解型肌肉中慢性缺氧会降低LCFA的最大氧化，这可以解释运动时对葡萄糖的依赖。
