Higher expression of denervation-responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA)

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Aging Cell Pub Date : 2024-06-03 DOI:10.1111/acel.14115
Cole J. Lukasiewicz, Gregory J. Tranah, Daniel S. Evans, Paul M. Coen, Haley N. Barnes, Zhiguang Huo, Karyn A. Esser, Xiping Zhang, Christopher Wolff, Kevin Wu, Nancy E. Lane, Steven B. Kritchevsky, Anne B. Newman, Steven R. Cummings, Peggy M. Cawthon, Russell T. Hepple
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Abstract

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

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在肌肉、活动能力和衰老(SOMMA)研究中,变性反应基因的高表达与肌肉体积和表现特征呈负相关。
随着年龄的增长,骨骼肌纤维会经历去神经支配和再神经支配的反复循环。大约在生命的第 8 个 10 年,神经再支配不再跟得上步伐,导致持续去神经支配的肌肉纤维累积,进而加速肌肉功能障碍。关于衰老过程中神经支配对重要临床结果的影响,目前还没有深入研究。肌肉、活动能力和衰老研究(SOMMA)是一项大型队列研究,主要目的是评估衰老肌肉生物学如何影响临床重要特征。利用从 575 名参与者的阔筋膜肌肉活检中获得的转录组学数据,我们选择了 49 个去神经支配反应基因,以深入了解 SOMMA 中去神经支配的负担,从而检验去神经支配反应基因的高表达与 SOMMA 参与者特征(包括步行 400 米的时间、体能(VO2 峰值)、最大线粒体呼吸、肌肉质量和体积以及腿部肌肉力量和功率)呈负相关的假设。与我们的假设一致的是,钙依赖性细胞间粘附糖蛋白(CDH15)、乙酰胆碱受体亚基(CHRNA1、CHRND、CHRNE)、促进神经再支配的糖蛋白(NCAM1)、调节肌肉组织的转录因子(RUNX1)和钠通道(SCN5A)的转录本水平升高与上述特征中的至少 3 个特征呈负相关。VO2峰值和最大呼吸量分别与15个和19个去神经支配反应基因有最强的负相关。总之,神经支配反应基因转录本的丰度是决定老龄化人类肌肉和活动能力结果的重要因素,这支持了确定新的治疗策略以恢复高龄神经支配的必要性。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
期刊最新文献
Issue Information Featured Cover Correction to ‘Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis’ RETRACTION: 1,25-Dihydroxyvitamin D exerts an antiaging role by activation of Nrf2-antioxidant signaling and inactivation of p16/p53-senescence signaling Issue Information
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