Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile.
FASEB J. 2021 Oct;35(10):e21933. doi: 10.1096/fj.202001593RR.
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 oxidative soleus muscle. However, in gastrocnemius muscle, 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 in gastrocnemius, but not in soleus muscle after a 4-week HFD feeding. This increased metabolic profile in gastrocnemius was paralleled by preserving autophagy flux, while autophagy flux in soleus was 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 in gastrocnemius. 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.
在肥胖症中，骨骼肌线粒体活性发生变化以应对增加的营养供应。自噬已被提出作为参与调节线粒体代谢的必要机制。然而，自噬在肥胖症期间对骨骼肌中线粒体适应性的贡献尚不清楚。在这里，我们表明，在高脂肪饮食（HFD）喂养后，小鼠的不同骨骼肌表现出不同调节的自噬，这可能调节线粒体活性。我们观察到，在高脂肪饮食喂养 4 周和 40 周后，氧化型比目鱼肌中的氧化磷酸化（OXPHOS）亚基和线粒体 DNA 含量增加。然而，在具有混合纤维类型组成的腓肠肌中，只有在高脂肪饮食喂养 40 周后，线粒体质量才增加。有趣的是，在高脂肪饮食喂养 4 周后，脂肪酸支持的线粒体呼吸在腓肠肌中增强，但在比目鱼肌中没有增强。腓肠肌中这种增加的代谢特征与自噬流的保持平行，而比目鱼肌中的自噬流减少。为了确定自噬在这种差异反应中的作用，我们使用了一种特异性在骨骼肌中部分缺失 Atg7 的自噬缺陷型小鼠模型（SkM-Atg7 小鼠）。我们观察到，Atg7 的减少导致骨骼肌中的自噬流减少，同时也减弱了在高脂肪饮食喂养下观察到的腓肠肌中脂肪酸支持的线粒体呼吸的增加。值得注意的是，SkM-Atg7 小鼠没有出现增加的线粒体积累。总之，我们的结果表明，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性，并且 Atg7 介导的自噬调节了线粒体呼吸能力，但不能调节其在肥胖症饮食中的含量。
