Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Genomics. 2021 Sep;113(5):2965-2976. doi: 10.1016/j.ygeno.2021.06.035. Epub 2021 Jun 30.
Exercise is believed to be beneficial for skeletal muscle functions across all ages. Regimented exercise is often prescribed as an effective treatment/prophylaxis for age-related loss of muscle mass and function, known as sarcopenia, and plays an important role in the maintenance of mobility and functional independence in the elderly. However, response to exercise declines with aging, resulting in limited gain of muscle strength and endurance. These changes likely reflect age-dependent alterations in transcriptional response underlying the muscular adaptation to exercise. The exact changes in gene expression accompanying exercise, however, are largely unknown, and elucidating them is of a great clinical interest for understanding and optimizing the exercise-based therapies for sarcopenia. In order to characterize the exercise-induced transcriptomic changes in aged muscle, a paired-end RNA sequencing was performed on rRNA-depleted total RNA extracted from the gastrocnemius muscles of 24 months-old mice after 8 weeks of regimented exercise (exercise group) or no formal exercise program (sedentary group). Differential gene expression analysis of aged skeletal muscle revealed upregulations in the group of genes involved in neurotransmission and neuroexcitation, as well as equally notable absence of anabolic gene upregulations in the exercise group. In particular, genes encoding the transporters and receptor components of glutaminergic transmission were significantly upregulated in exercised muscles, as exemplified by Gria 1, Gria 2 and Grin2c encoding glutamate receptor 1, 2 and 2C respectively, Grin1 and Grin2b encoding N-methyl-d-aspartate receptors (NMDARs), Nptx1 responsible for glutaminergic receptor clustering, and Slc1a2 and Slc17a7 regulating synaptic uptake of glutamate. These changes were accompanied by an increase in the post-synaptic density of NMDARs and acetylcholine receptors (AChRs), as well as their innervation at neuromuscular junctions (NMJs). These results suggest that neural responses predominate the adaptive response of aged skeletal muscle to exercise, and indicate a possibility that glutaminergic transmission at NMJs may be present and responsible for synaptic protection and neural remodeling accompanying the exercise-induced functional enhancement in aged skeletal muscle. In addition, the absence of upregulations in the anabolic pathways highlights them as the area of potential pharmacological targeting for optimizing exercise-led sarcopenia therapy.
运动被认为对各个年龄段的骨骼肌功能有益。有规律的运动常被作为一种有效的治疗/预防与年龄相关的肌肉质量和功能丧失的方法，这种现象被称为肌肉减少症，它在老年人的活动能力和功能独立性的维持中起着重要作用。然而，随着年龄的增长，对运动的反应能力会下降，导致肌肉力量和耐力的增长有限。这些变化可能反映了肌肉对运动适应性的转录反应随年龄的变化。然而，伴随着运动的基因表达的确切变化在很大程度上是未知的，阐明这些变化对于理解和优化肌肉减少症的运动治疗具有重要的临床意义。为了描述衰老肌肉中运动引起的转录组变化，对 24 个月大的小鼠经过 8 周有规律的运动（运动组）或没有正式的运动方案（久坐组）后，从比目鱼肌中提取的 rRNA 耗尽的总 RNA 进行了配对末端 RNA 测序。对衰老骨骼肌的差异基因表达分析显示，参与神经传递和神经兴奋的基因上调，而运动组中同样显著缺乏合成代谢基因的上调。特别是，编码谷氨酰胺传递的转运体和受体成分的基因显著上调，例如编码谷氨酸受体 1、2 和 2C 的 Gria1、Gria2 和 Grin2c、编码 N-甲基-D-天冬氨酸受体（NMDAR）的 Grin1 和 Grin2b、负责谷氨酸能受体聚集的 Nptx1 以及调节谷氨酸突触摄取的 Slc1a2 和 Slc17a7。这些变化伴随着 NMDAR 和乙酰胆碱受体（AChR）在后突触密度的增加，以及它们在神经肌肉接点（NMJ）的神经支配。这些结果表明，神经反应在衰老骨骼肌对运动的适应性反应中占主导地位，并表明 NMJ 处的谷氨酰胺传递可能存在，并负责伴随运动引起的衰老骨骼肌功能增强的突触保护和神经重塑。此外，合成代谢途径的上调缺失突出了它们作为优化运动诱导的肌肉减少症治疗的潜在药物靶点的区域。
