Matthews Jennifer R, Herat Lakshini Y, Schlaich Markus P, Matthews Vance B
Dobney Hypertension Centre, School of Biomedical Sciences-Royal Perth Hospital Unit, University of Western Australia, and Royal Perth Hospital Research Foundation, Crawley, WA 6000, Australia.
Dobney Hypertension Centre, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, WA 6000, Australia.
Biomedicines. 2024 Jul 1;12(7):1456. doi: 10.3390/biomedicines12071456.
The hyperactivation of the sympathetic nervous system (SNS) is linked to obesity, hypertension, and type 2 diabetes, which are characterized by elevated norepinephrine (NE) levels. Previous research has shown increased sodium-dependent glucose cotransporter 1 (SGLT1) protein levels in kidneys of hypertensive rodents, prompting investigation into the expression of SGLT1 in various tissues, such as skeletal muscle. This study aimed to assess (i) whether skeletal muscle cells and tissue express SGLT1 and SGLT2 proteins; (ii) if NE increases SGLT1 levels in skeletal muscle cells, and (iii) whether the skeletal muscle of neurogenically hypertensive mice exhibits increased SGLT1 expression. We found that (i) skeletal muscle cells and tissue are a novel source of the SGLT2 protein and that (ii) NE significantly elevated SGLT1 levels in skeletal muscle cells. As SGLT2 inhibition (SGLT2i) with Empagliflozin increased SGLT1 levels, in vivo studies with the dual inhibitor SGLT1/2i, Sotagliflozin were warranted. The treatment of neurogenically hypertensive mice using Sotagliflozin significantly reduced blood pressure. Our findings suggest that SNS activity upregulates the therapeutic target, SGLT1, in skeletal muscle, potentially worsening cardiometabolic control. As clinical trial data suggest cardiorenal benefits from SGLT2i, future studies should aim to utilize SGLT1i by itself, which may offer a therapeutic strategy for conditions with heightened SNS activity, such as hypertension, diabetes, and obesity.
交感神经系统（SNS）的过度激活与肥胖、高血压和2型糖尿病有关，这些疾病的特征是去甲肾上腺素（NE）水平升高。先前的研究表明，高血压啮齿动物肾脏中钠依赖性葡萄糖转运体1（SGLT1）蛋白水平升高，这促使人们对SGLT1在骨骼肌等各种组织中的表达进行研究。本研究旨在评估：（i）骨骼肌细胞和组织是否表达SGLT1和SGLT2蛋白；（ii）NE是否会增加骨骼肌细胞中SGLT1的水平；以及（iii）神经源性高血压小鼠的骨骼肌中SGLT1表达是否增加。我们发现：（i）骨骼肌细胞和组织是SGLT2蛋白的新来源；（ii）NE显著提高了骨骼肌细胞中SGLT1的水平。由于恩格列净抑制SGLT2（SGLT2i）会增加SGLT1水平，因此有必要对双重抑制剂SGLT1/2i索格列净进行体内研究。使用索格列净治疗神经源性高血压小鼠可显著降低血压。我们的研究结果表明，SNS活性上调了骨骼肌中的治疗靶点SGLT1，这可能会使心脏代谢控制恶化。由于临床试验数据表明SGLT2i对心肾有益，未来的研究应旨在单独使用SGLT1i，这可能为SNS活性增强的疾病（如高血压、糖尿病和肥胖症）提供一种治疗策略。
