Vidyadharan Vipin A, Betancourt Ancizar, Smith Craig, Blesson Chellakkan S, Yallampalli Chandra
Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA.
Agilent Technologies Inc., Santa Clara, CA 95051, USA.
Int J Mol Sci. 2024 Nov 29;25(23):12860. doi: 10.3390/ijms252312860.
A prenatal low-protein (LP) diet disrupts glucose homeostasis in adult offspring. Skeletal muscles are one of the main sites of glucose clearance, and mitochondria residing in the muscle fibers are central to glucose homeostasis. Our previous studies indicated that impaired mitochondrial health is central to dysregulated glucose metabolism in the gastrocnemius muscle of the LP-programmed female rats. In addition, dysfunctional mitochondria are often an indicator of underlying irregularities in energy metabolism and metabolic inflexibility. Therefore, this study examined the mitochondrial function and metabolic flexibility in the skeletal muscles of prenatal LP-programmed adult male rats. Pregnant Wistar rats were randomly allotted to a control diet (20% protein) or an isocaloric LP diet (6% protein). Standard laboratory rat chow was given to the dams and the pups after delivery and weaning. Gene and protein expressions, mtDNA copy number, and electron microscopy were assessed in gastrocnemius (GS) muscle, and the mitochondrial oxygen consumption rate was determined using isolated flexor digitorum brevis muscle fibers. The genes associated with mitochondrial outer membrane fusion, mitofusin1 and 2 (Mfn1 and Mfn2), fission (Fis1), and biogenesis (Pgc1B, Nrf1, and Esrra) were lower in the LP group. Further, our functional studies showed that the ATP-linked oxygen consumption rate (OCR), maximal, spare respiratory, and non-mitochondrial respiration-associated OCRs were lower in the LP rats. Further, the mRNA and protein expressions of Ndufb8, a key factor involved in the complex-I catalytic activity, were downregulated in the LP group. In addition, the expression of genes linked to mitochondrial pyruvate transport (Mpc1) and metabolism (Pdha1) was lower in the LP group. In contrast, the expression of mitochondrial fatty acid transporters (Cpt1a and Cpt2) was higher in the LP when compared to the control group. However, electron microscopic analysis exhibited no difference in the mitochondrial ultrastructure in the LP muscle compared to the control. Altogether, our results indicate that the LP diet affects the mitochondrial complex-I integrity and dynamics and leads to altered expression of genes associated with substrate oxidation and mitochondrial dysfunction in the skeletal muscle of the male LP offspring.
产前低蛋白（LP）饮食会破坏成年子代的葡萄糖稳态。骨骼肌是葡萄糖清除的主要部位之一，而肌纤维中的线粒体对于葡萄糖稳态至关重要。我们之前的研究表明，线粒体健康受损是LP编程雌性大鼠腓肠肌葡萄糖代谢失调的核心。此外，功能失调的线粒体通常是能量代谢潜在异常和代谢灵活性的指标。因此，本研究检测了产前LP编程成年雄性大鼠骨骼肌中的线粒体功能和代谢灵活性。将怀孕的Wistar大鼠随机分配到对照饮食（20%蛋白质）或等热量LP饮食（6%蛋白质）组。产后和断奶后给母鼠和幼崽喂食标准实验室大鼠饲料。对腓肠肌（GS）进行基因和蛋白质表达、线粒体DNA拷贝数及电子显微镜评估，并使用分离的趾短屈肌纤维测定线粒体氧消耗率。与线粒体外膜融合相关的基因，如线粒体融合蛋白1和2（Mfn1和Mfn2）、裂变相关基因（Fis1）以及生物发生相关基因（Pgc1B、Nrf1和Esrra）在LP组中较低。此外，我们的功能研究表明，LP大鼠的ATP偶联氧消耗率（OCR）、最大、备用呼吸及非线粒体呼吸相关OCR均较低。此外，参与复合体I催化活性的关键因子Ndufb8的mRNA和蛋白质表达在LP组中下调。此外，与线粒体丙酮酸转运（Mpc1）和代谢（Pdha1）相关的基因表达在LP组中较低。相比之下，与对照组相比，LP组中线粒体脂肪酸转运蛋白（Cpt1a和Cpt2）的表达较高。然而，电子显微镜分析显示，与对照组相比，LP组肌肉中的线粒体超微结构没有差异。总之，我们的结果表明，LP饮食会影响线粒体复合体I的完整性和动力学，并导致雄性LP子代骨骼肌中与底物氧化和线粒体功能障碍相关基因的表达改变。
