Heat Acclimation-Mediated Cross-Tolerance: Origins in within-Life Epigenetics?

The primary outcome of heat acclimation is increased thermotolerance, which stems from enhancement of innate cytoprotective pathways. These pathways produce "ON CALL" molecules that can combat stressors to which the body has never been exposed, via cross-tolerance mechanisms (heat acclimation-mediated cross-tolerance-HACT). The foundation of HACT lies in the sharing of generic stress signaling, combined with tissue/organ- specific protective responses. HACT becomes apparent when acclimatory homeostasis is achieved, lasts for several weeks, and has a memory. HACT differs from other forms of temporal protective mechanisms activated by exposure to lower "doses" of the stressor, which induce adaptation to higher "doses" of the same/different stressor; e.g., preconditioning, hormesis. These terms have been adopted by biochemists, toxicologists, and physiologists to describe the rapid cellular strategies ensuring homeostasis. HACT employs two major protective avenues: constitutive injury attenuation and abrupt post-insult release of help signals enhanced by acclimation. To date, the injury-attenuating features seen in all organs studied include fast-responding, enlarged cytoprotective reserves with HSPs, anti-oxidative, anti-apoptotic molecules, and HIF-1α nuclear and mitochondrial target gene products. Using cardiac ischemia and brain hypoxia models as a guide to the broader framework of phenotypic plasticity, HACT is enabled by a metabolic shift induced by HIF-1α and there are less injuries caused by Ca overload, via channel or complex-protein remodeling, or decreased channel abundance. Epigenetic markers such as post-translational histone modification and altered levels of chromatin modifiers during acclimation and its decline suggest that dynamic epigenetic mechanisms controlling gene expression induce HACT and acclimation memory, to enable the rapid return of the protected phenotype. In this review the link between physiological evidence and the associated cellular and molecular mechanisms leading to HACT and its difference from short-acting cross-tolerance strategies will be discussed.