Ischemic Conditioning and Exercise as an Example of the Overlap Between Beneficial Stress Response Mechanisms

I point out this interesting open access paper not as a suggestion that anyone should consider trying remote ischemic conditioning - one should adopt some form of calorie restriction and greater levels of regular exercise before embarking upon fancier hobbies - but rather because it is illustrative of the degree to which common stress response mechanisms overlap. Heat, exercise, ischemia, and lack of nutrients all share some of the same channels of signal and response that lead to cells undertaking greater maintenance or building more robust tissue structures. That in turn means that we already have a fairly good idea of the plausible bounds on beneficial results when it comes to therapies that use pharmaceutical or other means to induce stress responses. They will be able to move people closer to the life trajectory of a very healthy, well maintained body, but more than that seems unlikely to be attained via this strategy.

Thirty years ago, researchers first discovered the phenomenon of ischemic pre-conditioning in an animal experiment. The seminal discovery that brief episodes of ischemia followed by reperfusion could significantly reduce myocardial infarct size gave rise to the area of myocardial protection firstly and then propagated to multi-organ protection. Ischemic preconditioning has evolved into remote ischemic conditioning (RIC). Although the underlying mechanisms of RIC are still unclear, it was found to be safe and well tolerated in both patients and healthy volunteers.

The use of long-term repeated RIC comes with the expectation that RIC can play its protective roles consistently; this RIC treatment protocol is now called chronic RIC. Clinical studies have demonstrated that chronic RIC could reduce adverse clinical events and improve neurological function, which was rare in previous studies using a once-only RIC treatment protocol. Intriguingly, some sports specialists, inspired by the favorable effects of RIC on skeletal muscles and endothelial function, applied RIC to exercise training, as intense exercise has been demonstrated to lead to a form of cardiac and skeletal muscles ischemic insult. To date, RIC has been shown to improve the maximal performance in highly trained swimmers, enhance 5-km time trial performance and attenuate the submaximal level of blood lactate during the incremental running test. Therefore, RIC could improve exercise performance as does regular interval exercise training.

Given the similar time window of early and late phase protection seen with both exercise and RIC, and their comparable effects on improving exercise performance, it is reasonable to speculate that the underlying mechanisms of RIC likely overlap with those of exercise. Heat shock protein (HSP) 70 family, especially HSP72, has been demonstrated to be associated with cardioprotection. Previous studies found significantly increased HSP72 levels after acute aerobic exercise. Similarly, increased HSP72 has been reported after RIC stimulus. Studies have demonstrated that exercise promoted endothelial NO synthase activity, increased the production of NO and improved endothelial cell function. Similarly, chronic RIC has been demonstrated to significantly improve flow-mediated dilation and enhance endothelial NO synthase expression in patients with coronary heart disease.

Autophagy is a process for eliminating dysfunctional organelles and protein aggregates, which is a kind of endogenous protection and required for cellular survival and homeostasis in response to stress. Studies have found that protective effects of RIC on cell survival were mediated by autophagy pathway, and autophagy participants in RIC-induced protection. Exercise induces the adaptational response from multiple organs (primarily in skeletal muscle), which will benefit human body. Recently, autophagy has been found to be an essential process involved in conserving and recycling the cellular resources, an important process of the adaptation response.

Exercise has direct beneficial effects on the cellular immune system, and it can mobilize NK and T cells to circulation during exercise. The immune cell activity may also be influenced by the exercise-induced release of immune regulatory cytokines. Similarly, RIC has also been demonstrated to influence inflammatory response and immune cells, and these are the essential underlying mechanisms of RIC-induced protection. RIC reduces inflammatory gene expression and dramatically changes the immune response, which induces protection.

From the data available so far, it appears that chronic RIC mimics regular exercise. Further studies are however urgently needed to validate this phenomenon. However, there are still several hurdles for popularizing chronic RIC. Currently, different chronic RIC protocols are used in various studies, the periods of using chronic RIC vary from 1 week to 1 year, and its frequencies vary from twice daily to once every two weeks. Although chronic RIC benefits health and protects organs from injury, its optimal protocol is still unclear.



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