Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, L2S 3A1, Canada; Department of Kinesiology, Brock University, St. Catharines, ON, L2S 3A1, Canada.
Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, L2S 3A1, Canada; Department of Kinesiology, Brock University, St. Catharines, ON, L2S 3A1, Canada.
Biochem Biophys Res Commun. 2022 Oct 1;623:89-95. doi: 10.1016/j.bbrc.2022.07.062. Epub 2022 Jul 19.
Neurogranin (Ng) is a calmodulin (CaM) binding protein that negatively regulates calcineurin - a Ca/CaM-dependent phosphatase that can mitigate the slow-to-fast fibre type shift observed with muscle unloading. Here, we questioned whether heterozygous deletion of Ng (Ng) would enhance calcineurin activity, thereby minimizing the slow-to-fast fibre type shift caused by muscle unloading. As expected, soleus muscles from young adult (3-4 months old) Ng mice had lowered Ng content and enhanced calcineurin activity when compared to soleus muscles obtained from male age-matched wild-type (WT) mice. Two weeks after tenotomy surgery, where the soleus and gastrocnemius tendons were severed, soleus total fibre count were found to be similarly reduced across both genotypes. However, significant reductions in myofibre cross-sectional area were only found in WT mice and not Ng mice. Furthermore, while soleus muscles from both WT and Ng mice exhibited a slow-to-fast fibre type shift with tenotomy, soleus muscles from Ng mice, in both sham and tenotomized conditions, had a greater proportion of oxidative fibres (type I and IIA) compared with that of WT mice. Corresponding well with this, we found that soleus muscles from Ng mice were more fatigue resistant compared with those obtained from their WT counterparts. Collectively, these findings show that heterozygous Ng deletion increases calcineurin activation, preserves myofibre size in response to unloading, and promotes the oxidative fibre type to ultimately enhance fatigue resistance. This study demonstrates the role of Ng in regulating calcineurin in vivo and its influence on skeletal muscle form and function.
神经颗粒蛋白（Ng）是一种钙调蛋白（CaM）结合蛋白，可负向调节钙调磷酸酶 - 一种 Ca/CaM 依赖性磷酸酶，可减轻肌肉失用引起的慢肌向快肌纤维类型转变。在这里，我们质疑 Ng 杂合缺失（Ng）是否会增强钙调磷酸酶活性，从而最大限度地减少肌肉失用引起的慢肌向快肌纤维类型转变。正如预期的那样，与来自同龄雄性野生型（WT）小鼠的比目鱼肌相比，年轻成年（3-4 个月大）Ng 小鼠的比目鱼肌中的 Ng 含量降低，钙调磷酸酶活性增强。在跟腱切断术后两周，即切断比目鱼肌和腓肠肌肌腱后，发现两种基因型的比目鱼肌总纤维计数均相似减少。然而，仅在 WT 小鼠中发现肌纤维横截面积显著减少，而在 Ng 小鼠中未发现。此外，尽管 WT 和 Ng 小鼠的比目鱼肌在跟腱切断后都表现出慢肌向快肌纤维类型转变，但 Ng 小鼠的比目鱼肌（无论是假手术还是切断术）的氧化纤维（I 型和 IIA 型）比例都比 WT 小鼠高。与这一结果相符的是，我们发现 Ng 小鼠的比目鱼肌比 WT 小鼠的比目鱼肌更耐疲劳。总之，这些发现表明杂合 Ng 缺失增加钙调磷酸酶的激活，在肌肉失用的情况下保持肌纤维大小，并促进氧化纤维类型，最终增强疲劳抵抗力。这项研究表明 Ng 在调节体内钙调磷酸酶中的作用及其对骨骼肌形态和功能的影响。
