Genetic deletion of Kvβ2 (AKR6) causes loss of muscle function and increased inflammation in mice.

IF 3.3 Q2 GERIATRICS & GERONTOLOGY
Frontiers in aging Pub Date : 2023-06-12 eCollection Date: 2023-01-01 DOI:10.3389/fragi.2023.1175510
Ravikumar Manickam, Jazmine Virzi, Anish Potti, Feng Cheng, David W Russ, Srinivas M Tipparaju
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引用次数: 0

Abstract

The voltage-gated potassium channels (Kv) are complex ion channels with distinct roles in neurotransmission, electrical conductivity of the heart, and smooth and striated muscle functions. Previously, we demonstrated that deletion of Kvβ2 in mice results in decreased Pax7 protein levels, hindlimb muscles and body weights, and fiber type switching. In the present study, we tested the hypothesis that Kvβ2 regulates skeletal muscle function in mice. The young and old Kvβ2 knockout (KO) and wildtype (WT) mice were utilized to test the aging phenotype and skeletal muscle function. Consistent with our previous finding, we found a significant reduction in hindlimb skeletal muscles mass and body weight in young Kvβ2 KO mice, which was also significantly reduced in old Kvβ2 KO mice compared with age-matched WT mice. Forelimb grip strength, and the hindleg extensor digitorum longus (EDL) muscles force-frequency relations were significantly decreased in young and old Kvβ2 KO mice compared to age-matched WT mice. Analysis of transmission electron microscopy images of EDL muscles in young mice revealed a significant reduction in the sarcomere length for Kvβ2 KO vs. WT. Hematoxylin and eosin-stained tibialis anterior muscles cryosections displayed a significant decrease in the number of medium (2,000-4,000 µm2) and largest (>4,000 µm2) myofibers area in young Kvβ2 KO vs. WT mice. We also found a significant increase in fibrotic tissue area in young Kvβ2 KO mice compared with age-matched WT mice. Analysis of RNA Seq data of the gastrocnemius muscles (GAS) identified significant increase in genes involved in skeletal muscle development, proliferation and cell fate determination, atrophy, energy metabolism, muscle plasticity, inflammation, and a decrease in circadian core clock genes in young Kvβ2 KO vs. WT mice. Several genes were significantly upregulated (384 genes) and downregulated (40 genes) in young Kvβ2 KO mice compared to age-matched WT mice. Further, RT-qPCR analysis of the GAS muscles displayed a significant increase in pro-inflammatory marker Il6 expression in young Kvβ2 KO mice compared to age-matched WT mice. Overall, the present study shows that deletion of Kvβ2 leads to decreased muscles strength and increased inflammation.

Abstract Image

Abstract Image

Abstract Image

Kvβ2 (AKR6) 基因缺失会导致小鼠肌肉功能丧失和炎症加剧。
电压门控钾通道(Kv)是一种复杂的离子通道,在神经传递、心脏电导以及平滑肌和横纹肌功能中发挥着不同的作用。此前,我们曾证实,在小鼠体内缺失 Kvβ2 会导致 Pax7 蛋白水平下降、后肢肌肉和体重减轻以及纤维类型转换。在本研究中,我们检验了 Kvβ2 调节小鼠骨骼肌功能的假设。我们利用年轻和年老的 Kvβ2 基因敲除(KO)小鼠和野生型(WT)小鼠来测试小鼠的衰老表型和骨骼肌功能。与之前的发现一致,我们发现年轻的 Kvβ2 KO 小鼠后肢骨骼肌质量和体重显著下降,与年龄匹配的 WT 小鼠相比,年老的 Kvβ2 KO 小鼠后肢骨骼肌质量和体重也显著下降。与年龄匹配的WT小鼠相比,年轻和年老的Kvβ2 KO小鼠的前肢握力和后腿伸肌(EDL)的力-频率关系明显降低。对年轻小鼠 EDL 肌肉透射电子显微镜图像的分析表明,与 WT 小鼠相比,Kvβ2 KO 小鼠的肌节长度明显减少。经血栓素和伊红染色的胫骨前肌冷冻切片显示,Kvβ2 KO小鼠与WT小鼠相比,中等(2,000-4,000 µm2)和最大(>4,000 µm2)肌纤维面积的数量显著减少。我们还发现,与年龄匹配的 WT 小鼠相比,幼年 Kvβ2 KO 小鼠的纤维组织面积明显增加。对腓肠肌(GAS)的 RNA Seq 数据进行分析后发现,与 WT 小鼠相比,Kvβ2 KO 小鼠幼年期骨骼肌发育、增殖和细胞命运决定、萎缩、能量代谢、肌肉可塑性、炎症相关基因显著增加,而昼夜节律核心时钟基因减少。与年龄匹配的 WT 小鼠相比,幼年 Kvβ2 KO 小鼠的多个基因明显上调(384 个基因)和下调(40 个基因)。此外,GAS 肌肉的 RT-qPCR 分析显示,与年龄匹配的 WT 小鼠相比,Kvβ2 KO 小鼠的促炎症标志物 Il6 表达明显增加。总之,本研究表明,Kvβ2 基因缺失会导致肌肉力量下降和炎症增加。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
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