Pannérec Alice, Springer Margherita, Migliavacca Eugenia, Ireland Alex, Piasecki Mathew, Karaz Sonia, Jacot Guillaume, Métairon Sylviane, Danenberg Esther, Raymond Frédéric, Descombes Patrick, McPhee Jamie S, Feige Jerome N
Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015 Lausanne, Switzerland.
School of Healthcare Science, Manchester Metropolitan University, Manchester, UK.
Aging (Albany NY). 2016 Apr;8(4):712-29. doi: 10.18632/aging.100926.
Declining muscle mass and function is one of the main drivers of loss of independence in the elderly. Sarcopenia is associated with numerous cellular and endocrine perturbations, and it remains challenging to identify those changes that play a causal role and could serve as targets for therapeutic intervention. In this study, we uncovered a remarkable differential susceptibility of certain muscles to age-related decline. Aging rats specifically lose muscle mass and function in the hindlimbs, but not in the forelimbs. By performing a comprehensive comparative analysis of these muscles, we demonstrate that regional susceptibility to sarcopenia is dependent on neuromuscular junction fragmentation, loss of motoneuron innervation, and reduced excitability. Remarkably, muscle loss in elderly humans also differs in vastus lateralis and tibialis anterior muscles in direct relation to neuromuscular dysfunction. By comparing gene expression in susceptible and non-susceptible muscles, we identified a specific transcriptomic signature of neuromuscular impairment. Importantly, differential molecular profiling of the associated peripheral nerves revealed fundamental changes in cholesterol biosynthetic pathways. Altogether our results provide compelling evidence that susceptibility to sarcopenia is tightly linked to neuromuscular decline in rats and humans, and identify dysregulation of sterol metabolism in the peripheral nervous system as an early event in this process.
肌肉质量和功能的下降是老年人失去独立生活能力的主要驱动因素之一。肌肉减少症与众多细胞和内分泌紊乱有关，识别那些起因果作用并可作为治疗干预靶点的变化仍然具有挑战性。在本研究中，我们发现某些肌肉对与年龄相关的衰退存在显著的易感性差异。衰老的大鼠在后肢特异性地出现肌肉质量和功能丧失，但前肢则不然。通过对这些肌肉进行全面的比较分析，我们证明肌肉减少症的区域易感性取决于神经肌肉接头的碎片化、运动神经元支配的丧失以及兴奋性的降低。值得注意的是，老年人的肌肉损失在股外侧肌和胫骨前肌中也有所不同，这与神经肌肉功能障碍直接相关。通过比较易感性和不易感性肌肉中的基因表达，我们确定了神经肌肉损伤的特定转录组特征。重要的是，相关外周神经的差异分子谱分析揭示了胆固醇生物合成途径的根本变化。总之，我们的结果提供了令人信服的证据，表明肌肉减少症的易感性与大鼠和人类的神经肌肉衰退紧密相关，并确定外周神经系统中甾醇代谢的失调是这一过程中的早期事件。
