Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Bat Galim, Haifa 31096, Israel.
Department of Internal Medicine E, Rambam Health Care Campus, P.O. Box 9602, Bat Galim, Haifa 31096, Israel.
Int J Mol Sci. 2024 Jul 16;25(14):7789. doi: 10.3390/ijms25147789.
Excessive calorie intake leads to mitochondrial overload and triggers metabolic inflexibility and insulin resistance. In this study, we examined how attenuated p38α activity affects glucose and fat metabolism in the skeletal muscles of mice on a high-fat diet (HFD). Mice exhibiting diminished p38α activity (referred to as p38α) gained more weight and displayed elevated serum insulin levels, as well as a compromised response in the insulin tolerance test, compared to the control mice. Additionally, their skeletal muscle tissue manifested impaired insulin signaling, leading to resistance in insulin-mediated glucose uptake. Examination of muscle metabolites in p38α mice revealed lower levels of glycolytic intermediates and decreased levels of acyl-carnitine metabolites, suggesting reduced glycolysis and β-oxidation compared to the controls. Additionally, muscles of p38α mice exhibited severe abnormalities in their mitochondria. Analysis of myotubes derived from p38α mice revealed reduced mitochondrial respiratory capacity relative to the myotubes of the control mice. Furthermore, these myotubes showed decreased expression of Acetyl CoA Carboxylase 2 (ACC2), leading to increased fatty acid oxidation and diminished inhibitory phosphorylation of pyruvate dehydrogenase (PDH), which resulted in elevated mitochondrial pyruvate oxidation. The expected consequence of reduced mitochondrial respiratory function and uncontrolled nutrient oxidation observed in p38α myotubes mitochondrial overload and metabolic inflexibility. This scenario explains the increased likelihood of insulin resistance development in the muscles of p38α mice compared to the control mice on a high-fat diet. In summary, within skeletal muscles, p38α assumes a crucial role in orchestrating the mitochondrial adaptation to caloric surplus by promoting mitochondrial biogenesis and regulating the selective oxidation of nutrients, thereby preventing mitochondrial overload, metabolic inflexibility, and insulin resistance.
过量的卡路里摄入会导致线粒体过载，从而引发代谢灵活性和胰岛素抵抗。在这项研究中，我们研究了减弱的 p38α 活性如何影响高脂肪饮食（HFD）小鼠骨骼肌中的葡萄糖和脂肪代谢。与对照小鼠相比，p38α 活性减弱（称为 p38α）的小鼠体重增加更多，血清胰岛素水平升高，胰岛素耐量试验反应受损，其骨骼肌组织胰岛素信号受损，导致胰岛素介导的葡萄糖摄取抵抗。检查 p38α 小鼠的肌肉代谢物发现，糖酵解中间产物水平较低，酰基辅酶 A 代谢物水平降低，表明与对照相比，糖酵解和β-氧化减少。此外，p38α 小鼠的肌肉线粒体存在严重异常。与对照小鼠的肌管相比，p38α 小鼠的肌管中线粒体呼吸能力降低。此外，这些肌管中乙酰辅酶 A 羧化酶 2（ACC2）的表达减少，导致脂肪酸氧化增加和丙酮酸脱氢酶（PDH）的抑制性磷酸化减少，从而导致线粒体丙酮酸氧化增加。p38α 肌管中线粒体呼吸功能降低和不受控制的营养氧化所观察到的预期后果是线粒体过载和代谢灵活性。这种情况解释了与对照小鼠相比，p38α 小鼠在高脂肪饮食下肌肉中胰岛素抵抗发展的可能性增加。总之，在骨骼肌中，p38α 通过促进线粒体生物发生和调节营养物质的选择性氧化来协调对卡路里过剩的线粒体适应，从而防止线粒体过载、代谢灵活性和胰岛素抵抗。
