Greenwell Amanda A, Tabatabaei Dakhili Seyed Amirhossein, Gopal Keshav, Saed Christina T, Chan Jordan S F, Kazungu Mugabo Nick, Zhabyeyev Pavel, Eaton Farah, Kruger Jennifer, Oudit Gavin Y, Ussher John R
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.
Front Cardiovasc Med. 2022 Sep 23;9:997352. doi: 10.3389/fcvm.2022.997352. eCollection 2022.
Barth syndrome (BTHS) is a rare genetic disorder due to mutations in the gene, leading to impaired maturation of cardiolipin and thereby adversely affecting mitochondrial function and energy metabolism, often resulting in cardiomyopathy. In a murine model of BTHS involving short-hairpin RNA mediated knockdown of (TazKD mice), myocardial glucose oxidation rates were markedly reduced, likely secondary to an impairment in the activity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. Furthermore, TazKD mice exhibited cardiac hypertrophy with minimal cardiac dysfunction. Because the stimulation of myocardial glucose oxidation has been shown to alleviate diabetic cardiomyopathy and heart failure, we hypothesized that stimulating PDH activity would alleviate the cardiac hypertrophy present in TazKD mice. In order to address our hypothesis, 6-week-old male TazKD mice and their wild-type (WT) littermates were treated with dichloroacetate (DCA; 70 mM in the drinking water), which stimulates PDH activity via inhibiting PDH kinase to prevent inhibitory phosphorylation of PDH. We utilized ultrasound echocardiography to assess cardiac function and left ventricular wall structure in all mice prior to and following 6-weeks of treatment. Consistent with systemic activation of PDH and glucose oxidation, DCA treatment improved glycemia in both TazKD mice and their WT littermates, and decreased PDH phosphorylation equivalently at all 3 of its inhibitory sites (serine 293/300/232). However, DCA treatment had no impact on left ventricular structure, or systolic and diastolic function in TazKD mice. Therefore, it is unlikely that stimulating glucose oxidation is a viable target to improve BTHS-related cardiomyopathy.
巴斯综合征（BTHS）是一种罕见的遗传性疾病，由该基因的突变引起，导致心磷脂成熟受损，从而对线粒体功能和能量代谢产生不利影响，常导致心肌病。在涉及短发夹RNA介导的基因敲低的BTHS小鼠模型（TazKD小鼠）中，心肌葡萄糖氧化率显著降低，这可能继发于葡萄糖氧化的限速酶丙酮酸脱氢酶（PDH）活性受损。此外，TazKD小鼠表现出心脏肥大，但心脏功能障碍最小。由于已证明刺激心肌葡萄糖氧化可减轻糖尿病性心肌病和心力衰竭，我们推测刺激PDH活性将减轻TazKD小鼠中存在的心脏肥大。为了验证我们的假设，对6周龄的雄性TazKD小鼠及其野生型（WT）同窝小鼠用二氯乙酸（DCA；饮用水中70 mM）进行处理，DCA通过抑制PDH激酶来刺激PDH活性，以防止PDH的抑制性磷酸化。在治疗6周之前和之后，我们利用超声心动图评估所有小鼠的心脏功能和左心室壁结构。与PDH和葡萄糖氧化的全身激活一致，DCA治疗改善了TazKD小鼠及其WT同窝小鼠的血糖水平，并在其所有3个抑制位点（丝氨酸293/300/232）同等程度地降低了PDH磷酸化。然而，DCA治疗对TazKD小鼠的左心室结构、收缩和舒张功能没有影响。因此，刺激葡萄糖氧化不太可能是改善BTHS相关心肌病的可行靶点。
