衰老骨骼肌中的神经再支配失败。
Failed reinnervation in aging skeletal muscle.
机构信息
Research Institute of the McGill University Health Centre, EM2.2232, RI MUHC, 1001 Decarie Blvd, Montreal, QC Canada H4A 3J1 ; McGill Research Centre for Physical Activity and Health, McGill University, Montreal, QC Canada.
Research Institute of the McGill University Health Centre, EM2.2232, RI MUHC, 1001 Decarie Blvd, Montreal, QC Canada H4A 3J1 ; McGill Research Centre for Physical Activity and Health, McGill University, Montreal, QC Canada ; Department of Kinesiology and Physical Education, McGill University, Montreal, QC Canada.
出版信息
Skelet Muscle. 2016 Sep 1;6(1):29. doi: 10.1186/s13395-016-0101-y. eCollection 2016.
BACKGROUND
Skeletal muscle displays a marked accumulation of denervated myofibers at advanced age, which coincides with an acceleration of muscle atrophy.
METHODS
In this study, we evaluated the hypothesis that the accumulation of denervated myofibers in advanced age is due to failed reinnervation by examining muscle from young adult (YA) and very old (VO) rats and from a murine model of sporadic denervation secondary to neurotrypsin over-expression (Sarco mouse).
RESULTS
Both aging rat muscle and Sarco mouse muscle exhibited marked fiber-type grouping, consistent with repeating cycles of denervation and reinnervation, yet in VO muscle, rapsyn at the endplate increased and was associated with only a 10 % decline in acetylcholine receptor (AChR) intensity, whereas in Sarco mice, there was a decline in rapsyn and a 25 % decrease in AChR intensity. Transcripts of muscle-specific kinase (21-fold), acetylcholine receptor subunits α (68-fold), ε (threefold) and γ (47-fold), neural cell adhesion molecule (66-fold), and runt-related transcription factor 1 (33-fold) were upregulated in VO muscle of the rat, consistent with the marked persistent denervation evidenced by a large proportion of very small fibers (>20 %). In the Sarco mice, there were much smaller increases in denervation transcripts (0-3.5-fold) and accumulation of very small fibers (2-6 %) compared to the VO rat, suggesting a reduced capacity for reinnervation in aging muscle. Despite the marked persistent denervation in the VO rat muscle, transcripts of neurotrophins involved in promoting axonal sprouting following denervation exhibited no increase, and several miRNAs predicted to suppress neurotrophins were elevated in VO rat.
CONCLUSIONS
Our results support the hypothesis that the accumulation of denervated fibers with aging is due to failed reinnervation and that this may be affected by a limited neurotrophin response that mediates axonal sprouting following denervation.
背景
骨骼肌在高龄时会明显积累失神经的肌纤维，这与肌肉萎缩的加速同时发生。
方法
在这项研究中，我们通过检查来自年轻成年（YA）和非常年老（VO）大鼠的肌肉以及继发于神经丝氨酸蛋白酶过度表达的散发性失神经的鼠模型（Sarco 鼠），来评估高龄时失神经肌纤维积累是由于再神经支配失败的假说。
结果
衰老大鼠肌肉和 Sarco 鼠肌肉均表现出明显的纤维类型分组，与反复的失神经和再神经支配周期一致，但在 VO 肌肉中，终板上的rapsyn 增加，仅伴有乙酰胆碱受体（AChR）强度下降 10%，而在 Sarco 小鼠中，rapsyn 下降，AChR 强度下降 25%。肌肉特异性激酶（21 倍）、乙酰胆碱受体亚基 α（68 倍）、ε（3 倍）和 γ（47 倍）、神经细胞黏附分子（66 倍）和 runt 相关转录因子 1（33 倍）的转录物在大鼠 VO 肌肉中上调，与大量非常小纤维（>20%）所证明的明显持续失神经一致。在 Sarco 小鼠中，与 VO 大鼠相比，失神经转录物的增加幅度较小（0-3.5 倍），非常小纤维的积累较少（2-6%），表明衰老肌肉的再神经支配能力降低。尽管 VO 大鼠肌肉存在明显的持续失神经，但参与促进失神经后轴突发芽的神经营养因子的转录物没有增加，并且一些预测抑制神经营养因子的 miRNAs 在 VO 大鼠中升高。
结论
我们的结果支持这样的假说，即随着年龄的增长，失神经纤维的积累是由于再神经支配失败所致，而这可能受到限制的神经营养因子反应的影响，该反应介导失神经后的轴突发芽。
Zotero 插件