HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise
Abstract
The regulation of metabolism in peripheral tissues is intricately linked to circadian rhythms, with hypoxia-inducible factor-1α (HIF1α) implicated in modulating time-of-day-specific exercise responses. To investigate this relationship, we generated a skeletal muscle-specific HIF1α 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 HIF1α 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 HIF1α, skeletal muscle metabolism shifts toward oxidative pathways at ZT3, with notable alterations in glucose fate. These results establish HIF1α 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 HIF1α in coordinating circadian influences on metabolic health and exercise performance.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (11)
Amy M. Ehrlich
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Kirstin A. MacGregor
Integrative Physiology Department of Molecular Medicine and Surgery, Karolinska Institutet
Stephen P. Ashcroft
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Lewin Small
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Ali Altıntaş
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Alexander V. Chibalin
Integrative Physiology Department of Molecular Medicine and Surgery, Karolinska Institutet
Matthias Anagho-Mattanovich
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Ben Stocks
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Thomas Moritz
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Jonas T. Treebak
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Juleen R. Zierath
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen