Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA.
Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
Nat Commun. 2019 Jul 30;10(1):3412. doi: 10.1038/s41467-019-11265-y.
Skeletal muscle insulin resistance, decreased phosphatidylinositol 3-kinase (PI3K) activation and altered mitochondrial function are hallmarks of type 2 diabetes. To determine the relationship between these abnormalities, we created mice with muscle-specific knockout of the p110α or p110β catalytic subunits of PI3K. We find that mice with muscle-specific knockout of p110α, but not p110β, display impaired insulin signaling and reduced muscle size due to enhanced proteasomal and autophagic activity. Despite insulin resistance and muscle atrophy, M-p110αKO mice show decreased serum myostatin, increased mitochondrial mass, increased mitochondrial fusion, and increased PGC1α expression, especially PCG1α2 and PCG1α3. This leads to enhanced mitochondrial oxidative capacity, increased muscle NADH content, and higher muscle free radical release measured in vivo using pMitoTimer reporter. Thus, p110α is the dominant catalytic isoform of PI3K in muscle in control of insulin sensitivity and muscle mass, and has a unique role in mitochondrial homeostasis in skeletal muscle.
骨骼肌胰岛素抵抗、磷酸肌醇 3-激酶（PI3K）活性降低和线粒体功能改变是 2 型糖尿病的特征。为了确定这些异常之间的关系，我们创建了肌肉特异性敲除 PI3K 的 p110α 或 p110β 催化亚基的小鼠。我们发现，肌肉特异性敲除 p110α 的小鼠表现出胰岛素信号受损和肌肉萎缩，这是由于蛋白酶体和自噬活性增强所致。尽管存在胰岛素抵抗和肌肉萎缩，M-p110αKO 小鼠的血清肌肉生长抑制素减少，线粒体质量增加，线粒体融合增加，PGC1α 表达增加，尤其是 PCG1α2 和 PCG1α3。这导致线粒体氧化能力增强，肌肉 NADH 含量增加，体内使用 pMitoTimer 报告器测量的肌肉自由基释放增加。因此，p110α 是控制胰岛素敏感性和肌肉质量的肌肉中 PI3K 的主要催化同工型，在骨骼肌中线粒体稳态中具有独特的作用。
