Mason Steven D, Howlett Richard A, Kim Matthew J, Olfert I Mark, Hogan Michael C, McNulty Wayne, Hickey Reed P, Wagner Peter D, Kahn C Ronald, Giordano Frank J, Johnson Randall S
Molecular Biology Section, Division of Biology, School of Medicine, University of California, San Diego, USA.
PLoS Biol. 2004 Oct;2(10):e288. doi: 10.1371/journal.pbio.0020288. Epub 2004 Aug 24.
The physiological flux of oxygen is extreme in exercising skeletal muscle. Hypoxia is thus a critical parameter in muscle function, influencing production of ATP, utilization of energy-producing substrates, and manufacture of exhaustion-inducing metabolites. Glycolysis is the central source of anaerobic energy in animals, and this metabolic pathway is regulated under low-oxygen conditions by the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha). To determine the role of HIF-1alpha in regulating skeletal muscle function, we tissue-specifically deleted the gene encoding the factor in skeletal muscle. Significant exercise-induced changes in expression of genes are decreased or absent in the skeletal-muscle HIF-1alpha knockout mice (HIF-1alpha KOs); changes in activities of glycolytic enzymes are seen as well. There is an increase in activity of rate-limiting enzymes of the mitochondria in the muscles of HIF-1alpha KOs, indicating that the citric acid cycle and increased fatty acid oxidation may be compensating for decreased flow through the glycolytic pathway. This is corroborated by a finding of no significant decreases in muscle ATP, but significantly decreased amounts of lactate in the serum of exercising HIF-1alpha KOs. This metabolic shift away from glycolysis and toward oxidation has the consequence of increasing exercise times in the HIF-1alpha KOs. However, repeated exercise trials give rise to extensive muscle damage in HIF-1alpha KOs, ultimately resulting in greatly reduced exercise times relative to wild-type animals. The muscle damage seen is similar to that detected in humans in diseases caused by deficiencies in skeletal muscle glycogenolysis and glycolysis. Thus, these results demonstrate an important role for the HIF-1 pathway in the metabolic control of muscle function.
在运动的骨骼肌中，氧气的生理通量极大。因此，缺氧是肌肉功能的一个关键参数，影响着三磷酸腺苷（ATP）的产生、能量产生底物的利用以及导致疲劳的代谢物的生成。糖酵解是动物无氧能量的主要来源，并且这条代谢途径在低氧条件下受转录因子缺氧诱导因子1α（HIF-1α）调控。为了确定HIF-1α在调节骨骼肌功能中的作用，我们在骨骼肌中组织特异性地敲除了编码该因子的基因。在骨骼肌HIF-1α基因敲除小鼠（HIF-1α KO小鼠）中，显著的运动诱导基因表达变化减少或消失；糖酵解酶的活性也出现了变化。HIF-1α KO小鼠肌肉中线粒体限速酶的活性增加，这表明柠檬酸循环和脂肪酸氧化增加可能在补偿糖酵解途径流量的减少。运动的HIF-1α KO小鼠血清中肌肉ATP没有显著下降，但乳酸量显著减少，这一发现证实了上述情况。这种从糖酵解向氧化的代谢转变导致HIF-1α KO小鼠的运动时间增加。然而，重复的运动试验导致HIF-1α KO小鼠出现广泛的肌肉损伤，最终相对于野生型动物，运动时间大幅减少。所观察到的肌肉损伤与人类骨骼肌糖原分解和糖酵解缺陷所致疾病中检测到的损伤相似。因此，这些结果证明了HIF-1途径在肌肉功能代谢控制中的重要作用。
