Wang Mingrui, Azhati Samuhaer, Chen Hangyu, Zhang Yanyan, Shi Lijun
Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China.
School of Education, Beijing Sport University, Beijing 100084, China.
Genes (Basel). 2025 Jul 11;16(7):814. doi: 10.3390/genes16070814.
BACKGROUND/OBJECTIVES: Cardiac aging involves the progressive structural and functional decline of the myocardium. Endurance training is a well-recognized non-pharmacological intervention that counteracts this decline, yet the molecular mechanisms driving exercise-induced cardiac rejuvenation remain inadequately elucidated. This study aimed to identify key effector genes and regulatory pathways by integrating human cardiac aging transcriptomic data with multi-omic exercise response datasets.
A systems biology framework was developed to integrate age-downregulated genes ( = 243) from the GTEx human heart dataset and endurance-exercise-responsive genes ( = 634) from the MoTrPAC mouse dataset. Thirty-seven overlapping genes were identified and subjected to Enrichr for pathway enrichment, KEA3 for kinase analysis, and ChEA3 for transcription factor prediction. Candidate effector genes were ranked using ToppGene and ToppNet, with integrated prioritization via the FLAMES linear scoring algorithm.
Pathway enrichment revealed complementary patterns: aging-associated genes were enriched in mitochondrial dysfunction and sarcomere disassembly, while exercise-responsive genes were linked to protein synthesis and lipid metabolism. TTN, PDK family kinases, and EGFR emerged as major upstream regulators. NKX2-5, MYOG, and YBX3 were identified as shared transcription factors. SMPX ranked highest in integrated scoring, showing both functional relevance and network centrality, implying a pivotal role in mechano-metabolic coupling and cardiac stress adaptation.
By integrating cardiac aging and exercise-responsive transcriptomes, 37 effector genes were identified as molecular bridges between aging decline and exercise-induced rejuvenation. Aging involved mitochondrial and sarcomeric deterioration, while exercise promoted metabolic and structural remodeling. SMPX ranked highest for its roles in mechano-metabolic coupling and redox balance, with X-inactivation escape suggesting sex-specific relevance. Other top genes (e.g., KLHL31, MYPN, RYR2) form a regulatory network supporting exercise-mediated cardiac protection, offering targets for future validation and therapy.
背景/目的：心脏衰老涉及心肌结构和功能的逐渐衰退。耐力训练是一种公认的可对抗这种衰退的非药物干预措施，但运动诱导心脏年轻化的分子机制仍未得到充分阐明。本研究旨在通过整合人类心脏衰老转录组数据与多组学运动反应数据集来识别关键效应基因和调控途径。
开发了一个系统生物学框架，以整合来自GTEx人类心脏数据集的年龄下调基因（n = 243）和来自MoTrPAC小鼠数据集的耐力运动反应基因（n = 634）。鉴定出37个重叠基因，并对其进行通路富集分析（使用Enrichr）、激酶分析（使用KEA3）和转录因子预测（使用ChEA3）。使用ToppGene和ToppNet对候选效应基因进行排名，并通过FLAMES线性评分算法进行综合优先级排序。
通路富集揭示了互补模式：与衰老相关的基因富集于线粒体功能障碍和肌节解体，而运动反应基因与蛋白质合成和脂质代谢相关。肌联蛋白（TTN）、丙酮酸脱氢酶激酶（PDK）家族激酶和表皮生长因子受体（EGFR）成为主要的上游调节因子。NKX2 - 5、肌细胞生成素（MYOG）和YBX3被鉴定为共享转录因子。SMPX在综合评分中排名最高，显示出功能相关性和网络中心性，这意味着它在机械代谢偶联和心脏应激适应中起关键作用。
通过整合心脏衰老和运动反应转录组，鉴定出37个效应基因作为衰老衰退和运动诱导年轻化之间的分子桥梁。衰老涉及线粒体和肌节的恶化，而运动促进代谢和结构重塑。SMPX因其在机械代谢偶联和氧化还原平衡中的作用排名最高，X染色体失活逃逸表明其具有性别特异性相关性。其他顶级基因（如KLHL31、MYPN、RYR2）形成一个支持运动介导的心脏保护的调控网络，为未来的验证和治疗提供了靶点。
