Skeletal muscle type-specific mitochondrial adaptation to high-fat diet relies on differential autophagy modulation.
Skeletal muscle type-specific mitochondrial adaptation to high-fat diet relies on differential autophagy modulation.
复制标题
骨骼肌类型特异性线粒体对高脂肪饮食的适应依赖于差异自噬调节。
DOI：
10.1096/fj.202001593rr
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Espinosa,Alejandr
中科院分区：
文献类型：
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作者：
Morales,PabloE;Monsalves-Álvarez,Matías;Tadinada,SatyaMurthy;Harris,MatthewP;Ramírez-Sagredo,Andrea;Ortiz-Quintero,Jafet;Troncoso,MayarlingFrancisca;DeGregorio,Nicole;Calle,Ximena;Pereira,RenataO;Lira,VitorA;Espinosa,Alejandr
在肥胖症中，骨骼肌线粒体活性发生变化以科普增加的营养可用性。自噬已被认为是参与线粒体代谢调节的重要机制。尽管如此，自噬对肥胖期间骨骼肌线粒体适应的贡献尚不清楚。在这里，我们表明，在高脂饮食（HFD）喂养的反应中，小鼠不同的骨骼肌表现出差异调节的自噬，这可能会调节线粒体活性。我们观察到，在高脂饮食喂养4周和40周后，氧化性平滑肌中OXPHOS亚基和线粒体DNA含量增加。然而，具有混合纤维型组成的腓肠肌，线粒体质量仅在HFD喂养40周后增加。有趣的是，4周HFD喂养后，腓肠肌内脂肪酸支持的线粒体呼吸增强，但比目鱼肌内没有。这种增加的代谢概况inastrocnemius是通过保留自噬流量，而自噬流量在比目鱼减少。为了确定自噬在这种差异反应中的作用，我们使用了一种自噬缺陷小鼠模型，其中部分缺失了骨骼肌中的Atg 7（SkM‐ Atg 7 +/−小鼠）。我们观察到Atg 7减少导致骨骼肌中自噬通量减少，同时减弱了在腓肠肌内观察到的HFD诱导的脂肪酸支持的线粒体呼吸增加。值得注意的是，SkM-Atg 7 +/-小鼠没有出现线粒体积累增加。总之，我们的研究结果表明，HFD触发了具有不同纤维类型组成的骨骼肌中的特定线粒体适应，并且Atg 7介导的自噬调节线粒体呼吸能力，但不调节其对致肥胖饮食的反应。
In obesity, skeletal muscle mitochondrial activity changes to cope with increased nutrient availability. Autophagy has been proposed as an essential mechanism involved in the regulation of mitochondrial metabolism. Still, the contribution of autophagy to mitochondrial adaptations in skeletal muscle during obesity is unknown. Here, we show that in response to high‐fat diet (HFD) feeding, distinct skeletal muscles in mice exhibit differentially regulated autophagy that may modulate mitochondrial activity. We observed that after 4 and 40 weeks of high‐fat diet feeding, OXPHOS subunits and mitochondrial DNA content increased in the oxidativesoleusmuscle. However, ingastrocnemiusmuscle, which has a mixed fiber‐type composition, the mitochondrial mass increased only after 40 weeks of HFD feeding. Interestingly, fatty acid‐supported mitochondrial respiration was enhanced ingastrocnemius, but not insoleusmuscle after a 4‐week HFD feeding. This increased metabolic profile ingastrocnemiuswas paralleled by preserving autophagy flux, while autophagy flux insoleuswas reduced. To determine the role of autophagy in this differential response, we used an autophagy‐deficient mouse model with partial deletion of Atg7 specifically in skeletal muscle (SkM‐Atg7+/−mice). We observed that Atg7 reduction resulted in diminished autophagic flux in skeletal muscle, alongside blunting the HFD‐induced increase in fatty acid‐supported mitochondrial respiration observed ingastrocnemius. Remarkably, SkM‐Atg7+/−mice did not present increased mitochondria accumulation. Altogether, our results show that HFD triggers specific mitochondrial adaptations in skeletal muscles with different fiber type compositions, and that Atg7‐mediated autophagy modulates mitochondrial respiratory capacity but not its content in response to an obesogenic diet.