Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland.
Department of Molecular Biology, University of Gdansk, 80-308 Gdansk, Poland.
Cells. 2022 Aug 27;11(17):2662. doi: 10.3390/cells11172662.
Huntington's disease (HD) is a rare neurodegenerative disease that is accompanied by skeletal muscle atrophy and cardiomyopathy. Tissues affected by HD (central nervous system [CNS], skeletal muscle, and heart) are known to suffer from deteriorated cellular energy metabolism that manifests already at presymptomatic stages. This work aimed to test the effects of peroxisome proliferator-activated receptor (PPAR)-γ agonist-rosiglitazone on grip strength and heart function in an experimental HD model-on R6/1 mice and to address the mechanisms. We noted that rosiglitazone treatment lead to improvement of R6/1 mice grip strength and cardiac mechanical function. It was accompanied by an enhancement of the total adenine nucleotides pool, increased glucose oxidation, changes in mitochondrial number (indicated as increased citric synthase activity), and reduction in mitochondrial complex I activity. These metabolic changes were supported by increased total antioxidant status in HD mice injected with rosiglitazone. Correction of energy deficits with rosiglitazone was further indicated by decreased accumulation of nucleotide catabolites in HD mice serum. Thus, rosiglitazone treatment may not only delay neurodegeneration but also may ameliorate cardio- and myopathy linked to HD by improvement of cellular energetics.
亨廷顿病（HD）是一种罕见的神经退行性疾病，伴有骨骼肌萎缩和心肌病。已知 HD 受影响的组织（中枢神经系统[CNS]、骨骼肌和心脏）存在恶化的细胞能量代谢，这种代谢异常在症状前阶段就已经出现。本研究旨在测试过氧化物酶体增殖物激活受体（PPAR）-γ激动剂罗格列酮对实验性 HD 模型（R6/1 小鼠）中握力和心脏功能的影响，并探讨其机制。我们发现，罗格列酮治疗可改善 R6/1 小鼠的握力和心脏机械功能。同时伴随着总腺嘌呤核苷酸池的增加、葡萄糖氧化的增加、线粒体数量的变化（表现为柠檬酸合酶活性增加）以及线粒体复合物 I 活性的降低。这些代谢变化伴随着 HD 小鼠注射罗格列酮后总抗氧化状态的增加而得到支持。用罗格列酮纠正能量缺陷进一步表明，HD 小鼠血清中核苷酸分解产物的积累减少。因此，罗格列酮治疗不仅可以延缓神经退行性变，还可以通过改善细胞能量代谢来改善与 HD 相关的心肌病和肌病。
