Autophagy-associated atrophy and metabolic remodeling of the mouse diaphragm after short-term intermittent hypoxia.
Autophagy-associated atrophy and metabolic remodeling of the mouse diaphragm after short-term intermittent hypoxia.
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短期间歇性缺氧后，小鼠隔膜的自噬相关萎缩和代谢重塑。
DOI：
10.1371/journal.pone.0131068
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Petrof BJ
中科院分区：
文献类型：
--
作者：
Giordano C;Lemaire C;Li T;Kimoff RJ;Petrof BJ
短期间歇性缺氧（IH）在急性呼吸系统疾病患者中很常见。虽然长时间暴露于缺氧诱导骨骼肌萎缩和疲劳性增加，但对短期IH的反应尚不清楚。我们假设，膈肌和肢体肌肉将不同地适应短期IH，因为缺氧刺激通气并触发膈肌中的叠加运动刺激。我们确定了4天的IH（每天8小时，每小时30次发作，FiO 2最低值=6%）后，小鼠膈肌的结构，代谢和收缩特性，并比较了膈肌的反应，一个常用的研究参考肢体肌肉，胫骨前肌。结果指标包括肌纤维大小、肌肉蛋白水解（钙蛋白酶、泛素-蛋白酶体和自噬途径）测定、氧化应激和线粒体功能标志物、肌细胞内脂质和脂质代谢基因定量、I型肌球蛋白重链（MyHC）表达和体外收缩特性。IH 4天后，单独的膈肌显示出显著的萎缩（肌纤维尺寸减少30%），同时增加了LC 3B-II蛋白（2.4倍）和自噬途径的mRNA标记物（LC 3B，Gabarapl 1，Bnip 3），而两种肌肉中的活性钙蛋白酶和E3泛素连接酶（MuRF 1，atrogin-1）均未受影响。琥珀酸脱氢酶活性显着降低IH在这两种肌肉。然而，只有膈肌表现出增加肌细胞内脂滴（2.5倍）后IH，沿着上调基因与激活脂质代谢。此外，虽然隔膜在IH后立即显示出急性疲劳的证据，但它经历了向缓慢的I型MyHC表达纤维的适应性纤维类型转换，与体外重复刺激期间肌肉的更大内在耐力相关。短期IH诱导小鼠膈肌优先萎缩，同时增加自噬和与增强的抗疲劳性相关的快速代偿性代谢适应。
Short-term intermittent hypoxia (IH) is common in patients with acute respiratory disorders. Although prolonged exposure to hypoxia induces atrophy and increased fatigability of skeletal muscle, the response to short-term IH is less well known. We hypothesized that the diaphragm and limb muscles would adapt differently to short-term IH given that hypoxia stimulates ventilation and triggers a superimposed exercise stimulus in the diaphragm. We determined the structural, metabolic, and contractile properties of the mouse diaphragm after 4 days of IH (8 hours per day, 30 episodes per hour to a FiO2 nadir=6%), and compared responses in the diaphragm to a commonly studied reference limb muscle, the tibialis anterior. Outcome measures included muscle fiber size, assays of muscle proteolysis (calpain, ubiquitin-proteasome, and autophagy pathways), markers of oxidative stress and mitochondrial function, quantification of intramyocellular lipid and lipid metabolism genes, type I myosin heavy chain (MyHC) expression, and in vitro contractile properties. After 4 days of IH, the diaphragm alone demonstrated significant atrophy (30% decrease of myofiber size) together with increased LC3B-II protein (2.4-fold) and mRNA markers of the autophagy pathway (LC3B, Gabarapl1, Bnip3), whereas active calpain and E3 ubiquitin ligases (MuRF1, atrogin-1) were unaffected in both muscles. Succinate dehydrogenase activity was significantly reduced by IH in both muscles. However, only the diaphragm exhibited increased intramyocellular lipid droplets (2.5-fold) after IH, along with upregulation of genes linked to activated lipid metabolism. In addition, although the diaphragm showed evidence for acute fatigue immediately following IH, it underwent an adaptive fiber type switch toward slow type I MyHC-expressing fibers, associated with greater intrinsic endurance of the muscle during repetitive stimulation in vitro. Short-term IH induces preferential atrophy in the mouse diaphragm together with increased autophagy and a rapid compensatory metabolic adaptation associated with enhanced fatigue resistance.
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影响因子：
5.8
作者：
Goodpaster, BH;He, J;Kelley, DE
通讯作者：
Kelley, DE
影响因子：
3.5
作者：
Chabowski, Adrian;Gorski, Jan;Bonen, Arend
通讯作者：
Bonen, Arend
影响因子：
3.4
作者：
Mirrakhimov AE;Polotsky VY
通讯作者：
Polotsky VY
DOI：
10.1186/2046-7648-3-19
发表时间：
2014
期刊：
Extreme physiology & medicine
影响因子：
--
作者：
Horscroft JA;Murray AJ
通讯作者：
Murray AJ
影响因子：
4.8
作者：
Lira, Vitor A.;Okutsu, Mitsuharu;Yan, Zhen
通讯作者：
Yan, Zhen