Department of Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, Room 1011, Gonda South Rm 1011, 1500 E. Duarte Rd., Duarte, CA, 91010-3000, USA.
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA.
Cardiovasc Diabetol. 2023 Oct 27;22(1):294. doi: 10.1186/s12933-023-02020-1.
The PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to mitochondria in the myocardium. Mouse models of diabetes exhibit impaired mitochondrial AKT signaling but the implications of this on cardiac structure and function is unknown. We hypothesized that loss of mitochondrial AKT signaling is a critical step in cardiomyopathy and reduces cardiac oxidative phosphorylation.
To focus our investigation on the pathophysiological consequences of this mitochondrial signaling pathway, we generated transgenic mouse models of cardiac-specific, mitochondria-targeting, dominant negative AKT1 (CAMDAKT) and constitutively active AKT1 expression (CAMCAKT). Myocardial structure and function were examined using echocardiography, histology, and biochemical assays. We further investigated the underlying effects of mitochondrial AKT1 on mitochondrial structure and function, its interaction with ATP synthase, and explored in vivo metabolism beyond the heart.
Upon induction of dominant negative mitochondrial AKT1, CAMDAKT mice developed cardiac fibrosis accompanied by left ventricular hypertrophy and dysfunction. Cardiac mitochondrial oxidative phosphorylation efficiency and ATP content were reduced, mitochondrial cristae structure was lost, and ATP synthase structure was compromised. Conversely, CAMCAKT mice were protected against development of diabetic cardiomyopathy when challenged with a high calorie diet. Activation of mitochondrial AKT1 protected cardiac function and increased fatty acid uptake in myocardium. In addition, total energy expenditure was increased in CAMCAKT mice, accompanied by reduced adiposity and reduced development of fatty liver.
CAMDAKT mice modeled the effects of impaired mitochondrial signaling which occurs in the diabetic myocardium. Disruption of this pathway is a key step in the development of cardiomyopathy. Activation of mitochondrial AKT1 in CAMCAKT had a protective role against diabetic cardiomyopathy as well as improved metabolism beyond the heart.
PI3K/AKT 通路转导胰岛素的大部分代谢作用。除了胞质靶标外，胰岛素刺激的磷酸化 AKT 也在心肌中向线粒体易位。糖尿病的小鼠模型表现出线粒体 AKT 信号传导受损，但这对心脏结构和功能的影响尚不清楚。我们假设，线粒体 AKT 信号的丧失是心肌病的关键步骤，并降低心脏氧化磷酸化。
为了集中研究该线粒体信号通路的病理生理后果，我们生成了心脏特异性、线粒体靶向、显性负性 AKT1（CAMDAKT）和组成型活性 AKT1 表达（CAMCAKT）的转基因小鼠模型。使用超声心动图、组织学和生化测定来检查心肌结构和功能。我们进一步研究了线粒体 AKT1 对线粒体结构和功能的潜在影响，其与 ATP 合酶的相互作用，并探索了心脏以外的体内代谢。
在诱导显性负性线粒体 AKT1 后，CAMDAKT 小鼠发生心脏纤维化，伴有左心室肥大和功能障碍。心脏线粒体氧化磷酸化效率和 ATP 含量降低，线粒体嵴结构丢失，ATP 合酶结构受损。相反，当用高热量饮食挑战时，CAMCAKT 小鼠对糖尿病性心肌病的发展具有保护作用。线粒体 AKT1 的激活可保护心脏功能并增加心肌中的脂肪酸摄取。此外，CAMCAKT 小鼠的总能量消耗增加，伴随着脂肪减少和脂肪肝发展减少。
CAMDAKT 小鼠模拟了糖尿病心肌中发生的线粒体信号受损的影响。破坏该途径是心肌病发展的关键步骤。CAMCAKT 中线粒体 AKT1 的激活对糖尿病性心肌病具有保护作用，并改善了心脏以外的代谢。
