Cardiovascular Adaptive Homeostasis in Exercise

Abstract

Adaptive Homeostasis has been defined as, "The transient expansion or contraction of the homeostatic range in response to exposure to sub-toxic, non-damaging, signaling molecules or events, or the removal or cessation of such molecules or events." (Davies, 2016). I propose that one of the most significant examples of adaptive homeostasis may be the adaptation of the cardiovascular system to exercise training. In particular, endurance type training involves the generation of increased levels of free radicals such as ubisemiquinone, superoxide, nitric oxide, and other (non-radical) reactive oxygen species such as hydrogen peroxide (H₂O₂), in a repetitive manner, typically several times per week. As long as the training intensity and duration are sub-maximal and not exhaustive these reactive species do not cause damage, but rather activate signal transduction pathways to induce mitochondrial biogenesis-the foundation of increased exercise endurance. Particularly important are the NFκB and Nrf2 signal transduction pathways which respond to reactive oxygen and nitrogen species generated during exercise. As with other examples of adaptive homeostasis the effects are transient, lasting only as long as the training is maintained. Unfortunately, the ability to adapt to exercise training declines with age, perhaps as a result of impaired Nrf2 and NFκB signaling, as does adaptive homeostasis capacity in general. Since this is an Hypothesis/Theory Paper and not a review, I have not tried to provide a comprehensive discussion of all the literature relating to exercise adaptation and the cardiovascular system. Rather, I have attempted to develop the Hypothesis or Theory that adaptive homeostasis is the foundation for adaptation of the cardiovascular system to exercise training, largely based on work from my own laboratory, that of close collaborators, and that of key contributors over a period of almost 40 years.

Keywords: Nrf2; adaptive homeostasis; cardiovascular system; exercise; free radicals; mitochondria; redox regulation; signal transduction.

Figure 1

Adaptive homeostasis in exercise training. Reactive oxygen and nitrogen species such as ${\text{O}}_2^{•-}$, H₂O₂, and NO^• activate cytoplasmic signaling proteins such as Nrf2, NFκB, TFAM, and PGC1α to translocate to the cell nucleus where they bind to upstream promoter regions of hundreds of target genes to initiate transcription and (ultimately) translation. The protein products of these target genes include mitochondrial proteins encoded in the nucleus, leading to mitochondria biogenesis, and numerous other adaptive and protective proteins. These changes in gene expression and increased mitochondrial biogenesis (in addition to other metabolic alterations) lead to increased exercise endurance capacity. The training effect is a transient process of expanding the range of adaptive homeostasis and it only lasts as long as the training stimulus is maintained. If training is discontinued then detraining results in adaptive homeostasis returning the range of endurance capacity to pre-training levels.