Ma Sisi, Hubal Monica J, Morris Matthew C, Ross Leanna M, Huffman Kim M, Vann Christopher G, Moore Nadia, Hauser Elizabeth R, Bareja Akshay, Jiang Rong, Kummerfeld Eric, Barberio Matthew D, Houmard Joseph A, Bennett William C, Johnson Johanna L, Timmons James A, Broderick Gordon, Kraus Virginia B, Aliferis Constantin F, Kraus William E
Institute for Health Informatics (IHI), Academic Health Center, University of Minnesota, Minneapolis, MN 55455, United States.
Department of Kinesiology, Indiana University Indianapolis, Indianapolis, IN 46202, United States.
NAR Mol Med. 2025 Mar 28;2(2):ugaf010. doi: 10.1093/narmme/ugaf010. eCollection 2025 Apr.
Understanding how exercise improves whole-body insulin sensitivity (Si) involves complex molecular signaling. This study examines skeletal muscle gene expression changes related to Si, considering sex differences, exercise amount, and intensity to identify pharmacologic targets mimicking exercise benefits. Fifty-three participants from STRRIDE (Studies of Targeted Risk Reduction Interventions through Defined Exercise) I and II completed eight months of aerobic training. Gene expression was assessed via Affymetrix and Illumina technologies, and Si was measured using intravenous glucose tolerance tests. A novel discovery protocol integrating literature-derived and data-driven modeling identified causal pathways and direct transcriptional targets. In women, exercise amount primarily influenced transcription factor targets, which were generally inhibitory, while in men, exercise intensity drove activating targets. Common transcription factors included ATF1, CEBPA, BACH2, and STAT1. Si-related transcriptional targets included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key pathways mediating Si improvements were identified: estrogen signaling and protein kinase C (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets. The molecular pathways underlying Si improvements varied by sex and exercise parameters, highlighting potential skeletal muscle-specific drug targets such as EGFR to replicate the metabolic benefits of exercise.
了解运动如何改善全身胰岛素敏感性（Si）涉及复杂的分子信号传导。本研究考察了与Si相关的骨骼肌基因表达变化，考虑了性别差异、运动量和强度，以确定模拟运动益处的药物靶点。来自STRRIDE（通过明确运动进行有针对性的风险降低干预研究）I和II的53名参与者完成了8个月的有氧训练。通过Affymetrix和Illumina技术评估基因表达，并使用静脉葡萄糖耐量试验测量Si。一种整合文献衍生和数据驱动建模的新发现方案确定了因果途径和直接转录靶点。在女性中，运动量主要影响转录因子靶点，这些靶点通常具有抑制作用，而在男性中，运动强度驱动激活靶点。常见的转录因子包括ATF1、CEBPA、BACH2和STAT1。与Si相关的转录靶点包括强度驱动效应的TACR3和TMC7，以及运动量驱动效应的GRIN3B和EIF3B。确定了介导Si改善的两个关键途径：雌激素信号传导和蛋白激酶C（PKC）信号传导，两者都汇聚于表皮生长因子受体（EGFR）和其他相关靶点。Si改善的分子途径因性别和运动参数而异，突出了潜在的骨骼肌特异性药物靶点，如EGFR，以复制运动的代谢益处。
