Bean Linda A, Thomas Connor, Villa Juan F, Fitt Alexander J, Javier Areli Jannes S, Agrawal Akanksha, Whitney Hanna, Dos Santos Guilherme Nascimento, White Kenneth E, Huot Joshua R, Welc Steven S
Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
School of Medicine, Universidad CES, Medellin, Colombia.
bioRxiv. 2025 Jun 17:2025.06.11.659129. doi: 10.1101/2025.06.11.659129.
Muscle wasting and weakness are important clinical problems that impact quality of life and health span by restricting mobility and independence, and by increasing the risk for physical disability. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness. Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic enzymatic activity also increased. The composition of the soleus muscle was unaffected and myofiber caliber was reduced comparably in type I, IIa, and IIx fibers. Muscle contractile function declined in Klotho-deficient mice, as evidenced by reduced absolute twitch and torque, and decreased rates of contraction and relaxation. RNA-sequencing analysis identified increased transcriptional expression of synaptic and fetal sarcomeric genes, which prompted us to test effects on muscle innervation. Klotho-deficiency induced morphological remodeling of the neuromuscular junction, myofiber denervation, and a functional loss of motor units. Loss of motor units correlated with absolute torque. Collectively, our findings have uncovered a novel mechanism through which Klotho-deficiency leads to alterations to the muscle synapse affecting motor unit connectivity that likely influences muscle wasting and weakness.
肌肉萎缩和无力是重要的临床问题，通过限制活动能力和独立性以及增加身体残疾风险，影响生活质量和健康寿命。其分子基础尚未完全确定。在与肌肉萎缩相关的情况下，包括衰老、慢性肾病和肌病，Klotho的表达会下调。本研究的目的是探讨Klotho在调节肌肉萎缩和无力中的作用机制。Klotho基因缺失的小鼠体重、瘦体重、肌肉量和肌纤维直径均降低。在Klotho基因敲除小鼠的胫前肌中，IIa型肌纤维对大小变化具有抗性，并且肌肉组成有所不同，IIb型纤维浓度较高，而IIx型纤维减少。糖酵解酶活性也增加。比目鱼肌的组成未受影响，I型、IIa型和IIx型纤维的肌纤维直径均相应减小。Klotho基因缺失的小鼠肌肉收缩功能下降，表现为绝对抽搐和扭矩降低，以及收缩和舒张速率下降。RNA测序分析确定突触和胎儿肌节基因的转录表达增加，这促使我们测试其对肌肉神经支配的影响。Klotho基因缺失导致神经肌肉接头的形态重塑、肌纤维去神经支配和运动单位功能丧失。运动单位的丧失与绝对扭矩相关。总的来说，我们的研究结果揭示了一种新机制，通过该机制，Klotho基因缺失导致肌肉突触改变，影响运动单位连接性，这可能会影响肌肉萎缩和无力。
