健康个体中超长时间喂养对骨骼肌线粒体的影响。
Impact of prolonged overfeeding on skeletal muscle mitochondria in healthy individuals.
机构信息
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, 200 Lothrop Street, BST W1054, Pittsburgh, PA, 15261, USA.
Pennington Biomedical Research Center, Baton Rouge, LA, USA.
出版信息
Diabetologia. 2018 Feb;61(2):466-475. doi: 10.1007/s00125-017-4496-8. Epub 2017 Nov 17.
AIMS/HYPOTHESES: Reduced mitochondrial capacity in skeletal muscle has been observed in obesity and type 2 diabetes. In humans, the aetiology of this abnormality is not well understood but the possibility that it is secondary to the stress of nutrient overload has been suggested. To test this hypothesis, we examined whether sustained overfeeding decreases skeletal muscle mitochondrial content or impairs function.
METHODS
Twenty-six healthy volunteers (21 men, 5 women, age 25.3 ± 4.5 years, BMI 25.5 ± 2.4 kg/m) underwent a supervised protocol consisting of 8 weeks of high-fat overfeeding (40% over baseline energy requirements). Before and after overfeeding, we measured systemic fuel oxidation by indirect calorimetry and performed skeletal muscle biopsies to measure mitochondrial gene expression, content and function in vitro. Mitochondrial function in vivo was measured by P NMR spectroscopy.
RESULTS
With overfeeding, volunteers gained 7.7 ± 1.8 kg (% change 9.8 ± 2.3). Overfeeding increased fasting NEFA, LDL-cholesterol and insulin concentrations. Indirect calorimetry showed a shift towards greater reliance on lipid oxidation. In skeletal muscle tissue, overfeeding increased ceramide content, lipid droplet content and perilipin-2 mRNA expression. Phosphorylation of AMP-activated protein kinase was decreased. Overfeeding increased mRNA expression of certain genes coding for mitochondrial proteins (CS, OGDH, CPT1B, UCP3, ANT1). Despite the stress of nutrient overload, mitochondrial content and mitochondrial respiration in muscle did not change after overfeeding. Similarly, overfeeding had no effect on either the emission of reactive oxygen species or on mitochondrial function in vivo.
CONCLUSIONS/INTERPRETATION: Skeletal muscle mitochondria are significantly resilient to nutrient overload. The lower skeletal muscle mitochondrial oxidative capacity in human obesity is likely to be caused by reasons other than nutrient overload per se.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01672632.
目的/假设：在肥胖和 2 型糖尿病患者中，骨骼肌的线粒体容量已经降低。在人类中，这种异常的病因尚不清楚，但有人认为这是营养超负荷压力的继发结果。为了验证这一假说，我们研究了持续过度喂养是否会减少骨骼肌线粒体含量或损害其功能。
方法
26 名健康志愿者（21 名男性，5 名女性，年龄 25.3±4.5 岁，BMI 25.5±2.4kg/m）接受了一项强化饮食干预，即 8 周高脂肪喂养（超出基线能量需求的 40%）。在喂养前后，我们通过间接测热法测量全身燃料氧化，并进行骨骼肌活检，以测量线粒体基因表达、含量和体外功能。通过 P NMR 光谱法测量体内线粒体功能。
结果
在喂养期间，志愿者体重增加了 7.7±1.8kg（变化百分比为 9.8±2.3）。过度喂养增加了空腹游离脂肪酸、LDL-胆固醇和胰岛素浓度。间接测热法显示，对脂质氧化的依赖程度增加。在骨骼肌组织中，过度喂养增加了神经酰胺含量、脂滴含量和 perilipin-2 mRNA 表达。AMP 激活蛋白激酶的磷酸化减少。过度喂养增加了某些编码线粒体蛋白（CS、OGDH、CPT1B、UCP3、ANT1）的基因的 mRNA 表达。尽管受到营养超负荷的压力，肌肉中的线粒体含量和线粒体呼吸在过度喂养后并没有改变。同样，过度喂养对活性氧的产生或体内线粒体功能也没有影响。
结论/解释：骨骼肌线粒体对营养超负荷具有显著的抵抗力。人类肥胖中骨骼肌线粒体氧化能力降低的原因可能不仅仅是营养超负荷本身。
临床试验注册
ClinicalTrials.gov NCT01672632。
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