Circadian Clock Interaction with HIF1α Mediates Oxygenic Metabolism and Anaerobic Glycolysis in Skeletal Muscle

Abstract: Abstract Circadian clocks are internal timing systems that enable organisms to anticipate and adapt to daily environmental changes. These rhythms arise from a transcription-translation feedback loop in which CLOCK/BMAL1 regulate the expression of thousands of genes, including their repressors PER/CRY 1 . Disruption of circadian rhythms contributes to obesity, metabolic disease, and cancer 2-4 , yet how the clock maintains metabolic homeostasis remains limited. Here we report that the clock regulates oxidative metabolism through diurnal respiration of mitochondrial respiratory chain complex I. Genetic loss of the clock and high fat diet feeding in male mice led to reduced complex I respiration within adipocytes, leading to suppression of PPAR and insulin signaling pathways. In contrast, preserving complex I function maintained adipogenic and metabolic gene networks and protected against diet- and circadian-induced metabolic dysfunction independently of weight gain. These findings reveal that circadian disruption impairs metabolic health through mitochondrial complex I dysfunction, establishing clock control of complex I as a key regulator of transcriptional and metabolic homeostasis.

TL;DR: This study summarizes the literature on the nutritional protocols, emphasizing their impacts on bone and muscle biology, and identifies novel genes and signaling pathways involved in musculoskeletal biology.

Abstract: Additional file 3: Table S6. Details of the Excluded Literature.

Abstract: ABSTRACT Circadian rhythms are intrinsic 24‐h biological cycles that govern various physiological processes. In addition to the hypothalamic suprachiasmatic nucleus, the circadian system is organized in multiple peripheral tissues, such as the brain, heart, bone, liver, and lung. Emerging evidence suggests that disruptions in these rhythms, which are regulated by a network of clock genes, play pivotal roles in human health. A deeper understanding of the interplay between circadian rhythms and tissue homeostasis holds significant potential for the development of targeted therapies aimed at improving human health. This review explores the link between circadian rhythms and tissue homeostasis, delving into their biological functions, including influences on metabolic homeostasis, neuroendocrine signaling, immune and oxidative stress responses, tissue repair, and autophagy activity. It also summarizes the connections between circadian disruptions and circadian disruption‐related diseases, including degenerative diseases, cardiometabolic disorders, and cancers. Furthermore, this review offers valuable perspectives on the treatment of circadian disruption‐related diseases. By revealing the regulatory influence of circadian rhythms on human health and disease, this work aims to inspire the development of novel strategies for the prevention, diagnosis, and treatment of circadian disruption‐related diseases.

TL;DR: HIF plays a central role in the transcriptional response to changes in oxygen availability and is modulated by FIH1-mediated asparagine hydroxylation, and HIF-modulatory drugs are now being developed for diverse diseases.

TL;DR: Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology and rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of H IF dysregulation in chronic diseases, and investigating potential targeting of Hifs for therapeutic purposes.

TL;DR: An emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.

TL;DR: Advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes are reviewed and implications for rational therapeutics for these conditions are reviewed.