Mouse liver is more resistant than skeletal muscle to heat-induced apoptosis

摘要

During passive heat stress, shifting of blood flow from the hepato-splanchnic to peripheral regions produces less favorable physiological conditions in the liver than in the skeletal muscle. We were wondering if the two organs differ in susceptibility to heat injury and thus examined the effects of heat shock exposure on apoptotic and heat stress-related markers in the gastrocnemius muscle and liver of mice. During heat exposure, mice had a peak core body temperature of 41.1?±?0.7?°C. Heat-exposed mice showed higher levels of reactive oxygen species (ROS), cleaved caspases, fragmented DNA, and Drp1 protein expression in the gastrocnemius muscles than control mice. These changes were not observed in the livers of heat-exposed mice. Furthermore, the levels of glucocorticoid receptor, HSP70, and HSF1 proteins were significantly elevated in the gastrocnemius muscles of heat-exposed mice compared with that of control mice. The livers of heat-exposed mice also revealed increased expression of HSP70 but no changes in the other proteins. These results demonstrate that heat exposure induces significantly lower levels of the stress response and apoptosis in the liver than in the skeletal muscle of mice. The liver tissue resistance against heat stress is associated with low levels of heat-induced ROS production and mitochondrial fission protein expression. Keywords: Hyperthermia, Heat tolerance, Hepatic ischemia, Mitochondrial dynamics, DNM1LIntroductionHeat stress-induced changes vary widely between different organs, which may produce a less favorable physiological environment in some organs. Skeletal muscle and the liver account for two major portions of whole-body resting energy expenditure consisting of ~?20% and 17% in human and ~?30% and 20% in rat respectively (Rolfe and Brown 1997). During passive heat stress, blood flow distribution shifts from the hepato-splanchnic region (Crandall et al. 2008) to the skeletal muscle (Chiesa et al. 2016). This imposes challenges especially on liver function. Failure to have an adequate blood supply to meet tissue metabolic demand is one of the major causes of organ dysfunction/injury. Organ-related differences exist with respect to the coverage, severity, and reversibility of ischemia/reperfusion injury, indicating that ischemia of skeletal muscle is much better tolerated compared with that of other organs (Kalogeris et al. 2012). Whether the liver and the skeletal muscle differ in resistance against heat injury remains undetermined.Heat exposure can induce numerous cellular stress mediators that regulate both damaging and protective effects. Thus, the responses of these mediators likely determine the susceptibility to heat-induced injury and the outcome of heat exposure. During heat stress, at least two cellular events likely occur, an increase in mitochondrial energy production and unfolding of cytosolic chaperone complexes, resulting in the release of reactive oxygen species (ROS) and activation of heat shock factor 1 (HSF1) and glucocorticoid receptor (GR). Heat-induced ROS can trigger mitochondria-dependent apoptosis, leading to cell damage and tissue injury (Redza-Dutordoir and Averill-Bates 2016). We further demonstrated that heat-induced ROS and apoptosis in mouse skeletal muscle are associated with increased mitochondrial fission and are reduced following treatment with an inhibitor of the mitochondrial fission mediator dynamin-related protein 1 (Drp1) (Yu et al. 2016; Yu et al. 2018). The involvement of Drp1 in heat-induced apoptosis has yet to be tested in other tissues. Increases in tissue HSF1, HSP70, and GR protein levels have been observed following heat-induced hyperthermia in mice (Chen and Yu 2017; Islam et al. 2013) and rats (Cvoro et al. 1998). However, the link between the changes in these mediators and apoptotic susceptibility of different tissues in response to heat stress remains unclear.In the present study, we hypothesized that the liver and skeletal muscle have different susceptibilities to heat injury. Moreover, the levels of heat-induced stress responses in tissues also differ between these two organs. We therefore compared the effects of heat exposure on HSF1, HSP70, GR, Drp1, and apoptotic markers in the liver and gastrocnemius muscle of mice.Materials and methodsAnimalsMale adult C57BL/6J mice were purchased from Jackson Laboratories (Bar Harbor, ME), housed in a conventional animal facility (~?21?°C) with a 12-h light/dark cycle, and fed standard rodent chow diet and water ad libitum. All procedures performed on animals were reviewed and approved by the Uniformed Services University Institutional Animal Care and Use Committee in accordance with all applicable federal regulations governing the protection of animals in research. All mice were surgically implanted with a temperature transponder (G2 E-Mitter, Starr Life Sciences Corp, Oakmont, PA) in the abdominal cavity under anesthesia (Yu et al. 2018). At least 2?weeks was allowed for recover