Departments of Medicine and Molecular Physiology and Biophysics, Baylor College of Medicine, Suite 523-D2, Houston, TX, 77030, USA.
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
J Muscle Res Cell Motil. 2024 Dec;45(4):191-200. doi: 10.1007/s10974-024-09671-x. Epub 2024 Apr 29.
The muscular dystrophy with myositis (mdm) mouse model results in a severe muscular dystrophy due to an 83-amino-acid deletion in the N2A region of titin, an expanded sarcomeric protein that functions as a molecular spring which senses and modulates the response to mechanical forces in cardiac and skeletal muscles. ANKRD1 is one of the muscle ankyrin repeat domain proteins (MARPs) a family of titin-associated, stress-response molecules and putative transducers of stretch-induced signaling in skeletal muscle. The aberrant over-activation of Nuclear factor Kappa B (NF-κB) and the Ankyrin-repeat domain containing protein 1 (ANKRD1) occurs in several models of progressive muscle disease including Duchenne muscular dystrophy. We hypothesized that mechanical regulation of ANKRD1 is mediated by NF-κB activation in skeletal muscles and that this mechanism is perturbed by small deletion of the stretch-sensing titin N2A region in the mdm mouse. We applied static mechanical stretch of the mdm mouse diaphragm and cyclic mechanical stretch of CC myotubes to examine the interaction between NF-κΒ and ANKRD1 expression utilizing Western blot and qRTPCR. As seen in skeletal muscles of other severe muscular dystrophies, an aberrant increased basal expression of NF-κB and ANKRD1 were observed in the diaphragm muscles of the mdm mice. Our data show that in the mdm diaphragm, basal levels of NF-κB are increased, and pharmacological inhibition of NF-κB does not alter basal levels of ANKRD1. Alternatively, NF-κB inhibition did alter stretch-induced ANKRD1 upregulation. These data show that NF-κB activity is at least partially responsible for the stretch-induced expression of ANKRD1.
伴肌炎的肌营养不良症（mdm）小鼠模型由于肌联蛋白（titin）N2A 区的 83 个氨基酸缺失而导致严重的肌营养不良症，肌联蛋白是一种扩展的肌节蛋白，作为分子弹簧，感知和调节心脏和骨骼肌对机械力的反应。ANKRD1 是肌动蛋白重复域蛋白（MARP）家族的一种，该家族是肌联蛋白相关的应激反应分子，也是骨骼肌中拉伸诱导信号转导的假定传感器。核因子 Kappa B（NF-κB）和肌动蛋白重复域包含蛋白 1（ANKRD1）的异常过度激活发生在几种进行性肌肉疾病模型中，包括杜氏肌营养不良症。我们假设 ANKRD1 的机械调节是通过 NF-κB 在骨骼肌中的激活介导的，并且这种机制在 mdm 小鼠中拉伸感应肌联蛋白 N2A 区的小缺失时受到干扰。我们应用 mdm 小鼠膈肌的静态机械拉伸和 CC 肌管的循环机械拉伸，利用 Western blot 和 qRTPCR 检查 NF-κB 和 ANKRD1 表达之间的相互作用。正如在其他严重的肌肉营养不良症的骨骼肌中观察到的那样，在 mdm 小鼠的膈肌肌肉中观察到 NF-κB 和 ANKRD1 的异常基础表达增加。我们的数据表明，在 mdm 膈肌中，NF-κB 的基础水平增加，NF-κB 的药理学抑制不会改变 ANKRD1 的基础水平。相反，NF-κB 抑制确实改变了拉伸诱导的 ANKRD1 上调。这些数据表明 NF-κB 活性至少部分负责拉伸诱导的 ANKRD1 表达。
