尽管信号通路的反应相似,但老年大鼠骨骼肌萎缩后的再生能力受损。

Regrowth after skeletal muscle atrophy is impaired in aged rats, despite similar responses in signaling pathways.

作者信息

White Jena R, Confides Amy L, Moore-Reed Stephanie, Hoch Johanna M, Dupont-Versteegden Esther E

机构信息

Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky, 900 S Limestone, Lexington, KY 40536-0200, USA.

Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky, 900 S Limestone, Lexington, KY 40536-0200, USA.

出版信息

Exp Gerontol. 2015 Apr;64:17-32. doi: 10.1016/j.exger.2015.02.007. Epub 2015 Feb 12.

Abstract

Skeletal muscle regrowth after atrophy is impaired in the aged and in this study we hypothesized that this can be explained by a blunted response of signaling pathways and cellular processes during reloading after hind limb suspension in muscles from old rats. Male Brown Norway Fisher 344 rats at 6 (young) and 32 (old) months of age were subjected to normal ambulatory conditions (amb), hind limb suspension for 14 days (HS), and HS followed by reloading through normal ambulation for 14 days (RE); soleus muscles were used for analysis of intracellular signaling pathways and cellular processes. Soleus muscle regrowth was blunted in old compared to young rats which coincided with a recovery of serum IGF-1 and IGFBP-3 levels in young but not old. However, the response to reloading for p-Akt, p-p70s6k and p-GSK3β protein abundance was similar between muscles from young and old rats, even though main effects for age indicate an increase in activation of this protein synthesis pathway in the aged. Similarly, MAFbx mRNA levels in soleus muscle from old rats recovered to the same extent as in the young, while Murf-1 was unchanged. mRNA abundance of autophagy markers Atg5 and Atg7 showed an identical response in muscle from old compared to young rats, but beclin did not. Autophagic flux was not changed at either age at the measured time point. Apoptosis was elevated in soleus muscle from old rats particularly with HS, but recovered in HSRE and these changes were not associated with differences in caspase-3, -8 or -9 activity in any group. Protein abundance of apoptosis repressor with caspase-recruitment domain (ARC), cytosolic EndoG, as well as cytosolic and nuclear apoptosis inducing factor (AIF) were lower in muscle from old rats, and there was no age-related difference in the response to atrophy or regrowth. Soleus muscles from old rats had a higher number of ED2 positive macrophages in all groups and these decreased with HS, but recovered in HSRE in the old, while no changes were observed in the young. Pro-inflammatory cytokines in serum did not show a differential response with age to different loading conditions. Results indicate that at the measured time point the impaired skeletal muscle regrowth after atrophy in aged animals is not associated with a general lack of responsiveness to changes in loading conditions.

摘要

衰老过程中萎缩后的骨骼肌再生受损,在本研究中我们推测,这可以通过老年大鼠肌肉后肢悬吊再负荷期间信号通路和细胞过程的反应迟钝来解释。6个月龄(年轻)和32个月龄(老年)的雄性挪威棕大鼠分别处于正常活动状态(amb)、后肢悬吊14天(HS)以及后肢悬吊14天然后通过正常活动再负荷14天(RE);比目鱼肌用于分析细胞内信号通路和细胞过程。与年轻大鼠相比,老年大鼠比目鱼肌的再生受到抑制,这与年轻大鼠血清IGF-1和IGFBP-3水平的恢复一致,而老年大鼠则没有。然而,年轻和老年大鼠肌肉中p-Akt、p-p70s6k和p-GSK3β蛋白丰度对再负荷的反应相似,尽管年龄的主要影响表明老年动物中该蛋白质合成途径的激活增加。同样,老年大鼠比目鱼肌中MAFbx mRNA水平恢复到与年轻大鼠相同的程度,而Murf-1没有变化。自噬标志物Atg5和Atg7的mRNA丰度在老年大鼠肌肉中的反应与年轻大鼠相同,但beclin则不同。在所测量的时间点,两个年龄段的自噬通量均未改变。老年大鼠比目鱼肌中的凋亡增加,尤其是在HS组,但在HSRE组恢复,并且这些变化与任何组中caspase-3、-8或-9活性的差异无关。老年大鼠肌肉中具有半胱天冬酶募集结构域的凋亡抑制因子(ARC)、胞质EndoG以及胞质和核凋亡诱导因子(AIF)的蛋白丰度较低,并且在对萎缩或再生的反应中没有年龄相关差异。在所有组中,老年大鼠比目鱼肌中ED2阳性巨噬细胞的数量较多,这些巨噬细胞在HS组减少,但在老年大鼠的HSRE组恢复,而在年轻大鼠中未观察到变化。血清中的促炎细胞因子在不同负荷条件下对年龄没有差异反应。结果表明,在所测量的时间点,老年动物萎缩后骨骼肌再生受损与对负荷条件变化普遍缺乏反应性无关。

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