Sarto Fabio, Franchi Martino V, McPhee Jamie S, Stashuk Daniel W, Paganini Matteo, Monti Elena, Rossi Maira, Sirago Giuseppe, Zampieri Sandra, Motanova Evgeniia S, Valli Giacomo, Moro Tatiana, Paoli Antonio, Bottinelli Roberto, Pellegrino Maria A, De Vito Giuseppe, Blau Helen M, Narici Marco V
Department of Biomedical Sciences, University of Padova, Padova, Italy.
CIR-MYO Myology Centre, University of Padova, Padova, Italy.
J Cachexia Sarcopenia Muscle. 2024 Oct;15(5):1797-1810. doi: 10.1002/jcsm.13531. Epub 2024 Sep 5.
Degeneration of the motoneuron and neuromuscular junction (NMJ) and loss of motor units (MUs) contribute to age-related muscle wasting and weakness associated with sarcopenia. However, these features have not been comprehensively investigated in humans. This study aimed to compare neuromuscular system integrity and function at different stages of sarcopenia, with a particular focus on NMJ stability and MU properties.
We recruited 42 young individuals (Y) (aged 25.98 ± 4.6 years; 57% females) and 88 older individuals (aged 75.9 ± 4.7 years; 55% females). The older group underwent a sarcopenia screening according to the revised guidelines of the European Working Group on Sarcopenia in Older People 2. In all groups, knee extensor muscle force was evaluated by isometric dynamometry, muscle morphology by ultrasound and MU potential properties by intramuscular electromyography (iEMG). MU number estimate (iMUNE) and blood samples were obtained. Muscle biopsies were collected in a subgroup of 16 Y and 52 older participants.
Thirty-nine older individuals were non-sarcopenic (NS), 31 pre-sarcopenic (PS) and 18 sarcopenic (S). A gradual decrease in quadriceps force, cross-sectional area and appendicular lean mass was observed across the different stages of sarcopenia (for all P < 0.0001). Handgrip force and the Short Physical Performance Battery score also showed a diminishing trend. iEMG analyses revealed elevated near fibre segment jitter in NS, PS and S compared with Y (Y vs. NS and S: P < 0.0001; Y vs. PS: P = 0.0169), suggestive of age-related impaired NMJ transmission. Increased C-terminal agrin fragment (P < 0.0001) and altered caveolin 3 protein expression were consistent with age-related NMJ instability in all the older groups. The iMUNE was lower in all older groups (P < 0.0001), confirming age-related loss of MUs. An age-related increase in MU potential complexity was also observed. These observations were accompanied by increased muscle denervation and axonal damage, evinced by the increase in neural cell adhesion molecule-positive fibres (Y vs. NS: P < 0.0001; Y vs. S: P = 0.02) and the increase in serum concentration of neurofilament light chain (P < 0.0001), respectively. Notably, most of these MU and NMJ parameters did not differ when comparing older individuals with or without sarcopenia.
Alterations in MU properties, axonal damage, an altered innervation profile and NMJ instability are prominent features of the ageing of the neuromuscular system. These neuromuscular alterations are accompanied by muscle wasting and weakness; however, they appear to precede clinically diagnosed sarcopenia, as they are already detectable in older NS individuals.
运动神经元和神经肌肉接头（NMJ）的退化以及运动单位（MU）的丧失导致与肌肉减少症相关的年龄相关性肌肉萎缩和虚弱。然而，这些特征尚未在人类中得到全面研究。本研究旨在比较肌肉减少症不同阶段的神经肌肉系统完整性和功能，特别关注NMJ稳定性和MU特性。
我们招募了42名年轻人（Y组）（年龄25.98±4.6岁；57%为女性）和88名老年人（年龄75.9±4.7岁；55%为女性）。老年组根据欧洲老年人肌肉减少症工作组2的修订指南进行肌肉减少症筛查。在所有组中，通过等长测力法评估膝伸肌力量，通过超声评估肌肉形态，通过肌内肌电图（iEMG）评估MU电位特性。获得MU数量估计值（iMUNE）和血样。在16名年轻参与者和52名老年参与者的亚组中采集肌肉活检样本。
39名老年人为非肌肉减少症（NS），31名处于肌肉减少症前期（PS），18名患有肌肉减少症（S）。在肌肉减少症的不同阶段，观察到股四头肌力量、横截面积和四肢瘦体重逐渐下降（所有P<0.0001）。握力和简短身体功能量表评分也呈下降趋势。iEMG分析显示，与Y组相比，NS组、PS组和S组的近纤维节段抖动升高（Y组与NS组和S组比较：P<0.0001；Y组与PS组比较：P=0.0169），提示与年龄相关的NMJ传递受损。所有老年组中C末端聚集蛋白片段增加（P<0.0001）和小窝蛋白3蛋白表达改变与年龄相关的NMJ不稳定一致。所有老年组的iMUNE均较低（P<0.0001），证实与年龄相关的MU丧失。还观察到与年龄相关的MU电位复杂性增加。这些观察结果伴随着肌肉去神经支配和轴突损伤增加，分别表现为神经细胞粘附分子阳性纤维增加（Y组与NS组比较：P<0.0001；Y组与S组比较：P=0.02）和血清神经丝轻链浓度增加（P<0.0001）。值得注意的是，在比较有或没有肌肉减少症的老年人时，大多数这些MU和NMJ参数没有差异。
MU特性改变、轴突损伤、神经支配模式改变和NMJ不稳定是神经肌肉系统衰老的突出特征。这些神经肌肉改变伴随着肌肉萎缩和虚弱；然而，它们似乎先于临床诊断的肌肉减少症出现，因为在老年NS个体中已经可以检测到。
