Department of Pharmaceutical Sciences, University of South Florida College of Pharmacy, Tampa, FL, USA.
Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
Acta Physiol (Oxf). 2018 Oct;224(2):e13083. doi: 10.1111/apha.13083. Epub 2018 Jun 6.
Potassium channel accessory subunits (Kvβ) play a key role in cardiac electrical activity through ion channel modulation. In this study, we hypothesize that Kvβ2 regulates skeletal muscle growth and fibre phenotype via protein-protein interactions.
Kvβ2 knockout mouse model was used for morphometric, immunohistochemical and biochemical analysis to evaluate the role of Kvβ2 in skeletal muscle physiology.
Deletion of Kvβ2 gene in mice (Kvβ2 knockout, KO) leads to significant decrease in body weight along with skeletal muscle size. Key hindlimb muscles such as biceps, soleus and gastrocnemius were significantly smaller in size in KO mice compared to that of wild type. Morphometric measurements and histological analysis clearly point that the fibre size is decreased in each of the muscle type in KO compared with wild-type mice. In addition, Kvβ2 deletion contributes to fibre-type switching from fast to slow fibre as indicated by more abundant MHCI-expressing fibres in gastrocnemius and soleus muscles, which may underscore the smaller muscle size alongside increase in U3 ubiquitin ligase; NEDD4 expression. Using targeted siRNA knockdown approach, we identified that Kvβ2 knockdown does not affect the myoblasts proliferation. However, Pax7 expression was significantly decreased in 4-week-old gastrocnemius muscle, suggesting that cellular reserve for growth may be deficient in KO mice. This is further supported by decreased migratory capacity of C2C12 cells upon siRNA-targeted Kvβ2 knockdown.
Overall, this is the first report identifying that genetic deletion of Kvβ2 leads to decreased skeletal muscle size along with isotype switching.
钾通道辅助亚基（Kvβ）通过离子通道调节在心脏电活动中发挥关键作用。在这项研究中，我们假设 Kvβ2 通过蛋白-蛋白相互作用调节骨骼肌生长和纤维表型。
使用 Kvβ2 敲除小鼠模型进行形态计量学、免疫组织化学和生化分析，以评估 Kvβ2 在骨骼肌生理学中的作用。
小鼠 Kvβ2 基因缺失（Kvβ2 敲除，KO）导致体重显著下降，同时骨骼肌体积减小。与野生型相比，KO 小鼠的关键后肢肌肉，如二头肌、比目鱼肌和腓肠肌，体积明显减小。形态计量学测量和组织学分析清楚地表明，与野生型相比，KO 小鼠的每种肌肉纤维大小均减小。此外，Kvβ2 缺失导致纤维类型从快纤维向慢纤维转换，这表明在腓肠肌和比目鱼肌中 MHCI 表达的纤维更为丰富，这可能解释了肌肉体积减小以及 U3 泛素连接酶；NEDD4 表达增加的原因。使用靶向 siRNA 敲低方法，我们发现 Kvβ2 敲低并不影响成肌细胞的增殖。然而，Pax7 在 4 周龄腓肠肌中的表达显著降低，这表明 KO 小鼠的细胞生长储备可能不足。这进一步得到了 C2C12 细胞在靶向 Kvβ2 的 siRNA 敲低后迁移能力下降的支持。
总之，这是第一项确定 Kvβ2 基因缺失导致骨骼肌体积减小和同工型转换的报告。
