Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
Physiol Genomics. 2010 Feb 4;40(3):141-9. doi: 10.1152/physiolgenomics.00151.2009. Epub 2009 Nov 10.
Across numerous model systems, aging skeletal muscle demonstrates an impaired regenerative response when exposed to the same stimulus as young muscle. To better understand the impact of aging in a human model, we compared changes to the skeletal muscle transcriptome induced by unaccustomed high-intensity resistance loading (RL) sufficient to cause moderate muscle damage in young (37 yr) vs. older (73 yr) adults. Serum creatine kinase was elevated 46% 24 h after RL in all subjects with no age differences, indicating similar degrees of myofiber membrane wounding by age. Despite this similarity, from genomic microarrays 318 unique transcripts were differentially expressed after RL in old vs. only 87 in young subjects. Follow-up pathways analysis and functional annotation revealed among old subjects upregulation of transcripts related to stress and cellular compromise, inflammation and immune responses, necrosis, and protein degradation and changes in expression (up- and downregulation) of transcripts related to skeletal and muscular development, cell growth and proliferation, protein synthesis, fibrosis and connective tissue function, myoblast-myotube fusion and cell-cell adhesion, and structural integrity. Overall the transcript-level changes indicative of undue inflammatory and stress responses in these older adults were not mirrored in young subjects. Follow-up immunoblotting revealed higher protein expression among old subjects for NF-kappaB, heat shock protein (HSP)70, and IL-6 signaling [total and phosphorylated signal transducer and activator of transcription (STAT)3 at Tyr705]. Together, these novel findings suggest that young and old adults are equally susceptible to RL-mediated damage, yet the muscles of older adults are much more sensitive to this modest degree of damage-launching a robust transcriptome-level response that may begin to reveal key differences in the regenerative capacity of skeletal muscle with advancing age.
在许多模型系统中，衰老的骨骼肌在受到与年轻肌肉相同的刺激时，表现出受损的再生反应。为了更好地理解人类模型中衰老的影响，我们比较了未适应的高强度抵抗性负荷（RL）对年轻（37 岁）和老年（73 岁）成年人骨骼肌转录组的影响。所有受试者的血清肌酸激酶在 RL 后 24 小时升高了 46%，没有年龄差异，表明年龄对肌纤维膜损伤的程度相似。尽管如此，从基因组微阵列来看，老年组有 318 个独特的转录本在 RL 后差异表达，而年轻组只有 87 个。进一步的通路分析和功能注释表明，老年组中与应激和细胞损伤、炎症和免疫反应、坏死以及蛋白质降解相关的转录本上调，而与骨骼和肌肉发育、细胞生长和增殖、蛋白质合成、纤维化和结缔组织功能、成肌细胞-肌管融合和细胞-细胞黏附以及结构完整性相关的转录本表达（上调和下调）发生变化。总的来说，这些老年受试者中过度的炎症和应激反应的转录水平变化在年轻受试者中没有得到反映。进一步的免疫印迹显示，老年组中 NF-kappaB、热休克蛋白（HSP）70 和 IL-6 信号[总信号转导和转录激活因子（STAT）3 及其 Tyr705 磷酸化]的蛋白表达更高。总之，这些新发现表明，年轻和老年成年人对 RL 介导的损伤同样敏感，但老年成年人的肌肉对这种适度的损伤更为敏感，引发了强烈的转录水平反应，这可能开始揭示随着年龄的增长骨骼肌再生能力的关键差异。
