Mutation-dependent responses to sleep and exercise in clonal haematopoiesis

Key Points:

• The study investigates the effects of lifestyle interventions (sedentary, sleep fragmentation, and exercise) on clonal hematopoiesis (CH) in various genetically modified Ldlr−/− mice models, focusing on mutations in Jak2V617F, Tet2, p53, and Dnmt3a genes.
• Exercise influenced physical activity levels, sleep patterns, and inflammatory markers such as IL-1β and IL-6, with significant differences observed across mutant and wild-type bone marrow transplant groups; exercise generally reduced inflammatory cytokines and modified immune cell proliferation.
• Flow cytometry and single-cell RNA sequencing analyses revealed differential expansion and proliferation of mutant monocytes and macrophages in blood and aortic tissues, with lifestyle factors modulating these effects, particularly in Jak2V617F and Tet2 mutant models.
• Neutrophil activity, including NETosis, was assessed, showing that neutrophil depletion impacted monocyte expansion and atherosclerotic lesion development, highlighting the role of innate immune cells in CH-driven atherosclerosis under different lifestyle conditions.
• Pharmacological interventions targeting IL-1β and CLEC4E pathways demonstrated modulation of inflammatory responses and lesion characteristics, suggesting potential therapeutic avenues to mitigate CH-associated cardiovascular risks influenced by lifestyle factors.