a-preclinical-model-of-exertional-heat-stroke-in-mice

A Preclinical Model of Exertional Heat Stroke in Mice

Heat stroke is the most severe manifestation of heat-related illnesses. Classic heat stroke (CHS), also known as passive heat stroke, occurs at rest, ...

Skeletal muscles secrete a wide variety of immunologically active cytokines, but the functional significance of this response to in vivo innate immunity is not understood. We addressed this by knocking out the toll receptor adapter protein, Myd88, only in skeletal muscle fibers (skmMyd88KO), and followed male and female mice at 6 and 12 h after peritoneal injection of cecal slurry (CS), a model of polymicrobial sepsis. Because of a previously identified increase in mortality to CS injection, males received ~ 30% lower dose. At 12 h, skmMyd88KO caused significant reductions in a wide variety of pro- and anti-inflammatory plasma cytokines, e.g. TNFα, IL-1β and IL-10, compared to strain-matched controls in both males and females. Similar reductions were observed at 6 h in females. SkmMyd88KO led to ~ 40-50% elevations in peritoneal neutrophils at 6 and 12 h post CS in females. At 12 h post CS, skmMyd88KO increased peritoneal monocytes/macrophages and decreased %eosinophils and %basophils in females. SkmMyd88KO also led to significantly higher rates of mortality in female mice but not in males. In conclusion, the results suggest that skeletal muscle Myd88-dependent signal transduction can play functionally important role in normal whole body, innate immune inflammatory responses to peritoneal sepsis.

Skeletal muscle fibers play a functional role in host defense during sepsis in mice.

Exposure to exertional heat stroke (EHS) has been linked to increased long-term decrements of health. Epigenetic reprogramming is involved in the response to heat acclimation; however, whether the long-term effects of EHS are mediated by epigenetic reprogramming is unknown. In female mice, we observed DNA methylation reprogramming in bone marrow-derived (BMD) monocytes as early as 4 days of recovery from EHS and as late as 30 days compared with sham exercise controls. Whole blood, collected after 30 days of recovery from EHS, exhibited an immunosuppressive phenotype when challenged in vitro by lipopolysaccharide. After 30 days of recovery from EHS, BMD monocytes exhibited an altered in vitro heat shock response. The location of differentially methylated CpGs are predictive of both the immunosuppressive phenotype and altered heat shock responses.

Article	Year
Skeletal muscle fibers play a functional role in host defense during sepsis in mice. Scientific reports\| PubMed ID: 33795743	2021
Exertional heat stroke leads to concurrent long-term epigenetic memory, immunosuppression and altered heat shock response in female mice. The Journal of physiology\| PubMed ID: 33037634	2021

Jamal M. Alzahrani

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