朊蛋白糖蛋白对衰老过程中骨骼肌稳态的维持至关重要。

PrP Glycoprotein Is Indispensable for Maintenance of Skeletal Muscle Homeostasis During Aging.

作者信息

Liu Wenduo, Kieu Thi Thu Trang, Wang Zilin, Sim Hyun-Jaung, Lee Seohyeong, Lee Jeong-Chae, Park Yoonjung, Kim Sang Hyun, Kook Sung-Ho

机构信息

Department of Sports Science, College of Natural Science, Jeonbuk National University, Jeonju, Republic of Korea.

Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju, Republic of Korea.

出版信息

J Cachexia Sarcopenia Muscle. 2025 Feb;16(1):e13706. doi: 10.1002/jcsm.13706.

DOI:10.1002/jcsm.13706

PMID:39873124

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11773342/

Abstract

BACKGROUND

The cellular prion protein (PrP), a glycoprotein encoded by the PRNP gene, is known to modulate muscle mass and exercise capacity. However, the role of PrP in the maintenance and regeneration of skeletal muscle during ageing remains unclear.

METHODS

This study investigated the change in PrP expression during muscle formation using C2C12 cells and evaluated muscle function in Prnp wild-type (WT) and knock-out (KO) mice at different ages (1, 9 and 15 months). To determine the role of PrP in skeletal muscle homeostasis during ageing, we conducted regeneration experiments via cardiotoxin injection in Prnp mice to assess the effects of PrP deficiency on the senescence of satellite stem cells (SCs) and regenerative capacity in skeletal muscle.

RESULTS

Our data demonstrate that PrP expression increased significantly during muscle differentiation (p < 0.01), correlating with myogenin (immunofluorescence at the differentiation stage). PrP deficiency disrupted muscle homeostasis, leading to age-associated mitochondrial autophagy (Pink-1, +180%, p < 0.001; Parkin, +161%, p < 0.01) and endoplasmic reticulum stress (SERCA, -26%, p < 0.05; IRE1α, +195%, p < 0.001) while decreasing the level of mitochondrial biogenesis (SIRT-1, -50%, p < 0.01; PGC-1α, -36%, p < 0.05; VDAC, -27%, p < 0.001), and activated oxidative stress (serum myoglobin, +23%, p < 0.001; MDA, +23%, p < 0.05; NFκB, +117%, p < 0.05) during ageing, which accelerated reduced muscle growth or mass accumulation (tibialis anterior muscle mass, -23%, p < 0.001; gastrocnemius muscle mass, -30%, p < 0.001; muscle fibre size, -48%, p < 0.05; MSTN, +160%, p < 0.01; MAFbx, +83%, p < 0.05). Furthermore, PrP deficiency induced the senescence (β-galactosidase, +60%, p < 0.05; p16, +103%, p < 0.001) of SCs, which was directly related to the defect in muscle recovery, with the senescence-mediated enhancement of adipogenesis (PPARγ, +74%, p < 0.05) during the regeneration process after cardiotoxin-induced muscle injury.

CONCLUSIONS

Our findings demonstrate that PrP is indispensable for maintaining skeletal muscle homeostasis during ageing by modulating the functional integrity of mitochondria, ER and SCs.

摘要

背景

细胞朊蛋白（PrP）是一种由PRNP基因编码的糖蛋白，已知其可调节肌肉质量和运动能力。然而，PrP在衰老过程中对骨骼肌的维持和再生作用仍不清楚。

方法

本研究利用C2C12细胞研究肌肉形成过程中PrP表达的变化，并评估不同年龄（1、9和15个月）的Prnp野生型（WT）和敲除（KO）小鼠的肌肉功能。为了确定PrP在衰老过程中对骨骼肌稳态的作用，我们通过向Prnp小鼠注射心肌毒素进行再生实验，以评估PrP缺乏对卫星干细胞（SCs）衰老和骨骼肌再生能力的影响。

结果

我们的数据表明，PrP表达在肌肉分化过程中显著增加（p<0.01），与肌细胞生成素（分化阶段的免疫荧光）相关。PrP缺乏破坏了肌肉稳态，导致与年龄相关的线粒体自噬（Pink-1，增加180%，p<0.001；Parkin，增加161%，p<0.01）和内质网应激（SERCA，减少26%，p<0.05；IRE1α，增加195%，p<0.001），同时降低线粒体生物合成水平（SIRT-1，减少50%，p<0.01；PGC-1α，减少36%，p<0.05；VDAC，减少27%，p<0.001），并在衰老过程中激活氧化应激（血清肌红蛋白，增加23%，p<0.001；丙二醛，增加23%，p<0.05；NFκB，增加117%，p<0.05），这加速了肌肉生长或质量积累的减少（胫骨前肌质量，减少23%，p<0.001；腓肠肌质量，减少30%，p<0.001；肌纤维大小，减少48%，p<0.05；MSTN，增加160%，p<0.01；MAFbx，增加83%，p<0.05）。此外，PrP缺乏诱导SCs衰老（β-半乳糖苷酶，增加60%，p<0.05；p16，增加103%，p<0.001），这与肌肉恢复缺陷直接相关，在心肌毒素诱导的肌肉损伤后的再生过程中，衰老介导脂肪生成增强（PPARγ，增加74%，p<0.05）。