Review Erythrocytes as a Source of Exerkines, 2025, Misiti et al.

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Erythrocytes as a Source of Exerkines

Spoiler: Authors

Misiti, Francesco; Falese, Lavinia; Iannaccone, Alice; Diotaiuti, Pierluigi

Exercise activates many metabolic and signaling pathways in skeletal muscle and other tissues and cells, causing numerous systemic beneficial metabolic effects. Traditionally recognized for their principal role in oxygen (O2) transport, erythrocytes have emerged as dynamic regulators of vascular homeostasis.

Beyond their respiratory function, erythrocytes modulate vascular tone through crosstalk with other cells and tissues, particularly under hypoxia and physical exercise. This regulatory capacity is primarily mediated through the controlled release in the bloodstream of adenosine triphosphate (ATP) and nitric oxide (NO), two potent vasodilators that contribute significantly to matching oxygen supply with tissue metabolic demand. Emerging evidence suggests that many other erythrocyte-released molecules may act as additional factors involved in tissue-erythrocyte crosstalk.

This review highlights erythrocytes as active contributors to exercise-induced adaptations through their exocrine signaling.

Web | PDF | International Journal of Molecular Sciences | Open Access

 

[SNT Gatchaman]

Understanding exercise’s effects has been broadened, moving beyond the traditional cells. Research now highlights the impact of exercise on other tissues, like the liver, adipose tissue, and brain, and on systemic responses. This shift emphasizes the importance of inter-tissue communication and the role of muscle as an endocrine organ, secreting signaling molecules that affect distant tissues. Erythrocytes undergo significant mechanical and biochemical stress during exercise owing to increased cardiac output, augmented shear forces, and dynamic changes in blood rheology. These conditions stimulate the release of various erythrocyte-derived factors. Among these, adenosine triphosphate (ATP) and nitric oxide (NO) derivatives are particularly noteworthy.

Extracellular vesicles (EVs) shed by erythrocytes during physical activity may carry functional microRNAs, proteins, and lipids that contribute to intercellular communication, particularly in vascular and immune contexts

This review will elucidate the critical role of various molecules released from erythrocytes during exercise. These include ATP, nitric oxide/cyclic guanosine monophosphate, sphingosine-1-phosphate (S1P), lactate, reactive oxygen species (ROS), microRNA, and erythrocyte-derived microvesicles

Current evidence indicates that erythrocytes directly regulate O2 supply to human skeletal muscle during dynamic exercise. This theory aligns with observations made by two research teams that have shown erythrocytes release ATP and NO when there is a decrease in hemoglobin oxygen saturation.

Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that plays a significant role in various cellular processes, including growth, proliferation, differentiation, migration, and the suppression of apoptosis. It is found in high-nanomolar concentrations in human plasma, primarily bound to high-density lipoprotein (HDL) and albumin. In recent years, research has increasingly focused on the impact of exercise on S1P metabolism, revealing a critical, dynamic role for erythrocytes in this process. Erythrocytes are recognized as one of the principal sources of circulating S1P, alongside vascular endothelial cells

lactate is now recognized as a crucial metabolic intermediate, a mobile fuel for aerobic metabolism, and a potential mediator of redox status within and between cells. Furthermore, lactate debunks long-standing myths regarding lactate’s role in muscle fatigue, acidosis, and ischemic brain injury, suggesting important functions in wound repair, sepsis, and post-ischemic recovery instead. Erythrocytes, devoid of mitochondria and thus relying exclusively on glycolysis for ATP production, have become a primary source of lactate during exercise, particularly under conditions of heightened energy demand or oxygen limitation

Lactate operates as a potent signaling molecule in exercise, activating key cellular pathways such as the hypoxia-inducible factor-1α (HIF-1α) pathway and brain-derived neurotrophic factor (BDNF) release

Recent advancements have uncovered lactate’s role in epigenetic regulation, particularly through a novel post-translational modification termed histone lactylation, wherein lactate-derived lactyl groups are incorporated into histones, altering chromatin structure and modulating gene expression in response to metabolic stress. This finding has profound implications for understanding how exercise induces long-term adaptations at the genetic level

[…] fundamentally challenges the outdated “lactate threshold” model, which erroneously linked lactate accumulation solely to muscle fatigue and acidosis, instead highlighting its essential role as a master regulator of exercise physiology that integrates metabolic, cardiovascular, immune, and neurological responses to physical activity.