HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise

• 成果类型: Article
• 署名作者: Ehrlich, Amy M.; MacGregor, Kirstin A.; Ashcroft, Stephen P.; Small, Lewin; Altintas, Ali; Chibalin, Alexander V.; Anagho-Mattanovich, Matthias; Stocks, Ben; Moritz, Thomas; Treebak, Jonas T.; Zierath, Juleen R.
• 署名单位: University of Copenhagen; Karolinska Institutet; Karolinska Institutet
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10776
• DOI: 10.1073/pnas.2504080122
• 发表日期: 2025-07-15
• 关键词: mannose-6-phosphate; clock

摘要

The regulation of metabolism in peripheral tissues is intricately linked to circadian rhythms, with hypoxia-inducible factor-1 alpha (HIF1 alpha) implicated in modulating time-of-day-specific exercise responses. To investigate this relationship, we generated a skeletal muscle-specific HIF1 alpha knockout (KO) mouse model and performed extensive metabolic phenotyping and transcriptomic profiling under both basal conditions and following acute exercise during early rest (ZT3) and active (ZT15) phases. Our findings reveal that HIF1 alpha drives a more robust transcriptional and glycolytic response to exercise at ZT3, promoting glucose oxidation and mannose-6-phosphate production while potentially sparing fatty acid oxidation. In the absence of HIF1 alpha, skeletal muscle metabolism shifts toward oxidative pathways at ZT3, with notable alterations in glucose fate. These results establish HIF1 alpha as an important regulator of time-of-day-specific metabolic adaptations, integrating circadian and energetic signals to optimize substrate utilization. This work highlights the broader significance of HIF1 alpha in coordinating circadian influences on metabolic health and exercise performance.