Mohan Mithra Sudha, Sreedevi Aswani Sukumaran, Sakunthala Aparna Nandakumaran, Boban Puthenpura T, Sudhakaran Perumana R, Kamalamma Saja
1Department of Biochemistry, University of Kerala, Kariavattom, Thiruvananthapuram, Kerala 695581, India.
2Department of Biochemistry, Government College, Kariavattom, Thiruvananthapuram, Kerala 695581, India.
Physiol Int. 2023 Feb 27;110(1):1-18. doi: 10.1556/2060.2023.00128. Print 2023 Mar 10.
Hypothermic conditions enhance the incidence of cardiovascular diseases due to increased blood pressure. Cold-induced adaptive thermogenesis increased mitochondrial biogenesis and function in skeletal muscles and adipocytes. Here, we studied the effect of intermittent cold exposure on the regulators of cardiac mitochondrial biogenesis, function, and its regulation by SIRT-3. Intermittent cold exposed mice hearts showed normal histopathology with increased mitochondrial antioxidant and metabolic function, as evidenced by an increase in the activity and expression of MnSOD and SDH. A substantial increase in mitochondrial DNA copy number and increase in the expression of PGC-1α and its downstream targets NRF-1 and Tfam indicated the possibility of enhanced cardiac mitochondrial biogenesis and function on intermittent cold exposure. Increased mitochondrial SIRT-3 level and decreased total protein lysine acetylation indicate increased sirtuin activity in cold exposed mice hearts. Ex vivo cold mimic using norepinephrine showed a significant increase in PGC-1α, NRF-1, and Tfam levels. AGK-7, a SIRT-3 inhibitor, reversed the norepinephrine-induced upregulation of PGC-1α and NRF-1, indicating the role of SIRT-3 on the production of PGC-1α and NRF-1. Inhibition of PKA with KT5720 in norepinephrine treated cardiac tissue slices indicates the role of PKA in regulating the production of PGC-1α and NRF-1. In conclusion, intermittent cold exposure upregulated the regulators of mitochondrial biogenesis and function through PKA and SIRT-3 mediated pathway. Our results emphasize the role of intermittent cold-induced adaptive thermogenesis in overcoming chronic cold-induced cardiac damage.
低温状况会因血压升高而增加心血管疾病的发病率。冷诱导适应性产热增加了骨骼肌和脂肪细胞中的线粒体生物合成及功能。在此，我们研究了间歇性冷暴露对心脏线粒体生物合成、功能的调节因子以及SIRT-3对其调节作用的影响。间歇性冷暴露的小鼠心脏显示组织病理学正常，线粒体抗氧化和代谢功能增强，锰超氧化物歧化酶（MnSOD）和琥珀酸脱氢酶（SDH）的活性及表达增加证明了这一点。线粒体DNA拷贝数大幅增加以及过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）及其下游靶点核呼吸因子1（NRF-1）和线粒体转录因子A（Tfam）的表达增加表明，间歇性冷暴露可能增强了心脏线粒体的生物合成及功能。冷暴露小鼠心脏中线粒体SIRT-3水平升高且总蛋白赖氨酸乙酰化水平降低，表明冷暴露小鼠心脏中沉默调节蛋白活性增加。使用去甲肾上腺素进行的体外冷模拟显示PGC-1α、NRF-1和Tfam水平显著升高。SIRT-3抑制剂AGK-7逆转了去甲肾上腺素诱导的PGC-1α和NRF-1上调，表明SIRT-3在PGC-1α和NRF-1产生中的作用。在去甲肾上腺素处理的心脏组织切片中用KT5720抑制蛋白激酶A（PKA）表明PKA在调节PGC-1α和NRF-1产生中的作用。总之，间歇性冷暴露通过PKA和SIRT-3介导的途径上调了线粒体生物合成及功能的调节因子。我们的结果强调了间歇性冷诱导适应性产热在克服慢性冷诱导心脏损伤中的作用。
