**3. Mechanisms of exercise-induced preconditioning (EP)**

## **3.1 About the cardiovascular system**

*Cardiorespiratory Fitness*

physical exercise.

after exercise involve:

athletes.

long-term memory.

In addition, other non-ischemic stimuli have been studied to protect the heart, such as hypoxia [7], cell stretching [8], accelerated cardiac pacemaking [8] and

Exercise has been used as therapy for the treatment of stable ischemic vascular

b.increase in phosphorylation and expression of endothelial nitric oxide synthase [9];

Something that has to be clear when we talk about ischemic preconditioning is its dependence on the intensity of the stimulus (ischemia) and its duration, under this principle we can establish adequate protocols for the treatment of cardiovascular and muscular diseases; as well as, to improve the physical performance of the

Physical exercise challenges the organism to maintain stable conditions of the internal environment (homeostasis), against hypoxic conditions, oxidative stress and tissue nutrient deficiency. It is a condition of physiological stress, to be carried out continuously and through appropriate physical training programs provides benefits in the body, ranging from better control of blood glucose levels to better

There are multiple studies of the benefit of exercise in health, in all the virtues of exercise are praised. The result is obvious, improves and maintains the physical

It has direct effects on muscle strengthening and cardiovascular capacity, in addition to the systemic effects involved with the release of substances into the bloodstream or the tissue that contribute to the preconditioning of the heart and

The biochemical and physiological advantages conferred by exercise-induced preconditioning can serve to improve exercise performance. Although not all studies achieve this result, it is important not to forget that the participation of mediators produced and released during physical exercise and that are responsible for the

This chapter focuses on discussing the physiological mechanisms that are produced following an exercise-induced preconditioning protocol, especially those that relate to the cardiovascular system, skeletal muscle and physical performance.

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fitness, health and wellness of the person who performs it.

skeletal muscle can be attributed to exercise.

beneficial effects in the body.

**2. Research methodology**

syndrome, where it has been observed that it improves perfusion in ischemic tissues. Some mechanisms involved in improving the perfusion of ischemic tissues

a. shear stress-associated improvement of endothelial function [9];

c.decrease in vascular oxidative stress; and

d.collateral formation of vascular tissue.

**28**

The different cardiac affections, including myocardial infarction and ischemic heart diseases, are the main trigger of a high worldwide mortality, which originates in the sedentary lifestyle, chronic hyperglycemia and atherosclerosis. Although vigorous exercise itself induces a temporary hypoxia that causes damage to the myocardium, EP regulates down-pathological biomarkers and increases physiological biomarkers in both the pre-and post-myocardial infarction phase [10].

The protective effects of physical exercise on the cardiovascular system are carried out on cerebral blood flow, vascular endothelium, vascular vasodilation, endothelial progenitor cells, collateral circulation and cardiac muscle.

Despite the traditional knowledge of the benefits of aerobic exercise in health, it has not yet been introduced in the clinical setting. Knowing the benefits of exercise in cardiovascular and cerebrovascular diseases can encourage more patients with cerebral infarction and myocardial infarction and people with high-risk factors, to accept exercise interventions for prevention and treatment, and to health professionals to include exercise therapies as adjuvants in pharmacological treatment and even as independent therapies [11].

It is believed that early aerobic exercise has the potential to be a precautionary strategy for myocardial injury after myocardial infarction, through the regulation of the expression of proteins related to antioxidants and proteins associated with mitochondria [12].

In the heart one of the main harmful events produced by an insult is myocardial injury. Where, the protective role of EP has been reported, through the down regulation of KATP channels and the reduction of autophagy [13].

A mechanism of classic myocardial injury is damage by reperfusion, where, it has been reported that EP decreases oxidative stress, inflammatory cytokines and apoptosis, and increases the serum bioavailability of NO. These mechanisms are regulated by the GSK-3β pathway [14].

Interestingly, KATP channel opener drugs have been linked to cardioprotective events, where an increase in reactive oxygen species (ROS) has been reported, which downregulates the activity and expression of calcium channels in the tissue. Cardiac, which can mitigate the evolution of reperfusion damage. The positive regulation of ROS is related to the uncoupling of the respiratory chain, mainly in cardiomyocytes. Exercise, being a systemic event, activates complex mechanisms responsible for regulating body physiology, such as the vascular release of NO, which contributes to keeping the mechanical power of the heart regulated. On the other hand, as we know, an exacerbated increase in ROS, can generate tissue damage through mechanisms of cellular autophagy, so it is likely that time is a regulatory factor and of great importance in EP protocols. It is very difficult to perform an isolated study of the physiological role of EP, physiology seen as a complex

system challenges us to explain the phenomena from an integrative perspective that analyzes the phenomenon and its interactions with negative and positive regulation mechanisms.

From the therapeutic point of view the possible implications of PE, can contribute to improve the treatment of cardiovascular diseases, it has been reported that in a training protocol with vibration, increases cardiac tolerance to reperfusion injury after ischemia, decreases the size of the infarction and cardiac arrhythmias and facilitates spontaneous defibrillation [15]. These data suggest that exercise helps to regulate the participation of the electrical conduction system after a cardiac insult, the mechanisms by which this happens has not yet been elucidated.

It is known that the early response to a moderate and/or exacerbated cardiac insult eventually results in the generation of cardiac hypertrophy (increase in the volume of cardiomyocytes), which if not compensated, can progress to heart failure. Exercise has been related to a type of beneficial hypertrophy known as physiological hypertrophy, in which, far from having repercussions that compromise cardiac capacity, they improve it. On the other hand, there is pathological hypertrophy, which is linked to the development of myocardial scar and low cardiac capacity.

Treatments for cardiac hypertrophy are related to stopping the causal stimulus, which prevents its progression. In this sense, recently, PE has been reported to attenuate pathological cardiac hypertrophy by increasing the functional capacity of the cardiovascular system, through the MAPK pathway [16]. Probably this protective effect is related to the systemic increase of ROS, one of the main stimuli that regulate the MAPK pathway.

On the other hand, the level of autophagy activated during EP may be partially involved in the cardioprotective effects, maintaining a basal level of normal autophagy in the myocardium during the subsequent exhaustive exercise [17]. This ability of the EP to activate autophagy processes helps to sense the cellular metabolic processes, thus maintaining the homeostasis of cardiomycites.

Although in general, it is believed that preconditioning is directly triggered by a brief ischemia–reperfusion. It is known that brief ischemia produces transient dilatation (or stretching) of the heart. Therefore, it has been postulated that the stretching of the myocardium may be responsible for preconditioning, through the ion channels activated by stretching [18]. This idea can be supported indirectly by the fact that in chronic exercise, by increasing endothelial shear stress, increases NO production and ECNOS gene expression and can contribute to the beneficial effects of exercise in the cardiovascular system (ie say, antihypertensive) [19]. Although, as mentioned above, to say that the protective effect of preconditioning is due to a particular mechanism and not to a complex process, it is risky and simplistic.

The beneficial role of exercise on the cardiovascular system inevitably involves the regulation of vasodilation and vasoconstriction. In this sense, in stable coronary artery disease (CAD), exercise has been used as a treatment due to its endotheliumdependent vasodilator capacity, induced by acetylcholine. The molecular mechanism involved is through the phosphorylation of the eNOS-induced for Akt pathway [9]. This study demonstrates the role of exercise as a therapy in cardiovascular diseases, its actual use in therapy and the mechanism of action involved. To the extent that EP protocols are standardized and establish molecular relationships between the preconditioning processes, progress may be made in the non-pharmacological and/or combined treatment (drugs and exercise) of cardiovascular diseases.

Not only has it been linked to EP for the treatment of cardiovascular diseases, but it has also been shown to be useful for the treatment of doxorubicin poisoning (DOX), where it has been described that 2 weeks of EP are sufficient to prevent cardiorespiratory dysfunction associated with DOX and prevent mitochondrial

**31**

channels [26].

*Ischemic Preconditioning in Cardiac and Skeletal Muscle Induced by Exercise*

environments for cell insertion and even in organ transplants.

evaluate therapies and make adjustments to obtain the expected results.

dysfunction by reducing mitochondrial DOX accumulation [20]. The role of PE in poisoning processes can focus the bases to study its implications in pharmacokinetics and thus establish therapies with better efficiency and fewer adverse reactions

In addition, in a novel way, it has been described that PE induces a pro-angiogenic medium that can increase the therapeutic effects of stem cells derived from adipose tissue in cardiac remodeling after myocardial infarction [21], so its potential in genetic medicine, it is promising and can contribute to generating favorable tissue

Recently, it has been described that training with 12-week exercises in patients with heart failure mitigates ischemic injury due to endothelial reperfusion, protection mechanisms can be linked to PE [22]. This result is the first of its kind in a disease as complex as heart failure, so in a few years it is highly probable that within the treatment schemes for cardiovascular diseases exercise protocols are recommended. The challenge for health professionals is still great. Multidisciplinary groups must be established to develop and execute the protocols, monitor patients,

Skeletal muscle represents one of the most abundant tissues of the organism, for many years its mechanical and structural role has been studied, without studying its role in the regulation and maintenance of energy metabolism, release of humoral factors, regulation of oxidative stress, among others. Physical exercise represents the participation of the cardiovascular, respiratory and naturally skeletal muscle systems. For this reason, it is not to be expected that the protective role of the EP will positively impact the skeletal tissue. The mechanisms involved in the production of the beneficial effects of preconditioning in skeletal muscle are not yet clear, although it has recently been shown to decrease skeletal muscle atrophy induced by the discharge of the hind limbs (HU) and the mechanism that can participate it is through HDAC4/Gadd45α [23]. Although, interestingly, the mechanisms of physical training to reduce muscle atrophy are associated with the biogenesis, function and redox balance of mitochondria, the same mechanism involved in preconditioning [24]. The redox mechanism seems to be common in preconditioning processes regardless of white tissue, probably not the only shared mechanism, but certainly unlike the cardiac muscle, in skeletal muscle hypertrophy represents a greater

On the other hand, the mechanisms involved in changes in the markers of muscle damage and the parameters associated with running economy (ER) are not related, that is, increasing the tissue damage in skeletal muscle does not improve the ER [25]. However, it is likely that in order to represent an improvement in the ER, a

EP decreases arterial circulation in skeletal muscle, this confers hypoxia in the tissue. It has been reported that hypoxic preconditioning (HPC) can protect the function of respiratory skeletal muscle during reoxygenation through signaling cascades sensitive to redox mechanisms and the regulation of mitochondrial

The protective effect of EP on skeletal muscle can be used for the treatment of muscular atrophy and strengthening of muscle tissue. It is still necessary to study the mechanisms that can contribute to improve it and optimize the protocols that

On the other hand, preconditioning reduces the fatigue associated with repeated

exercise speed [27], however, it is still necessary to establish exercise protocols

*DOI: http://dx.doi.org/10.5772/intechopen.88309*

and/or drug interactions.

**3.2 About skeletal muscle**

capacity for energy regulation.

chronic protocol must be performed.

are adapted to the physiological needs of patients.

*Ischemic Preconditioning in Cardiac and Skeletal Muscle Induced by Exercise DOI: http://dx.doi.org/10.5772/intechopen.88309*

dysfunction by reducing mitochondrial DOX accumulation [20]. The role of PE in poisoning processes can focus the bases to study its implications in pharmacokinetics and thus establish therapies with better efficiency and fewer adverse reactions and/or drug interactions.

In addition, in a novel way, it has been described that PE induces a pro-angiogenic medium that can increase the therapeutic effects of stem cells derived from adipose tissue in cardiac remodeling after myocardial infarction [21], so its potential in genetic medicine, it is promising and can contribute to generating favorable tissue environments for cell insertion and even in organ transplants.

Recently, it has been described that training with 12-week exercises in patients with heart failure mitigates ischemic injury due to endothelial reperfusion, protection mechanisms can be linked to PE [22]. This result is the first of its kind in a disease as complex as heart failure, so in a few years it is highly probable that within the treatment schemes for cardiovascular diseases exercise protocols are recommended. The challenge for health professionals is still great. Multidisciplinary groups must be established to develop and execute the protocols, monitor patients, evaluate therapies and make adjustments to obtain the expected results.

### **3.2 About skeletal muscle**

*Cardiorespiratory Fitness*

mechanisms.

capacity.

regulate the MAPK pathway.

system challenges us to explain the phenomena from an integrative perspective that analyzes the phenomenon and its interactions with negative and positive regulation

From the therapeutic point of view the possible implications of PE, can contribute to improve the treatment of cardiovascular diseases, it has been reported that in a training protocol with vibration, increases cardiac tolerance to reperfusion injury after ischemia, decreases the size of the infarction and cardiac arrhythmias and facilitates spontaneous defibrillation [15]. These data suggest that exercise helps to regulate the participation of the electrical conduction system after a cardiac insult,

It is known that the early response to a moderate and/or exacerbated cardiac insult eventually results in the generation of cardiac hypertrophy (increase in the volume of cardiomyocytes), which if not compensated, can progress to heart failure. Exercise has been related to a type of beneficial hypertrophy known as physiological hypertrophy, in which, far from having repercussions that compromise cardiac capacity, they improve it. On the other hand, there is pathological hypertrophy, which is linked to the development of myocardial scar and low cardiac

Treatments for cardiac hypertrophy are related to stopping the causal stimulus,

On the other hand, the level of autophagy activated during EP may be partially involved in the cardioprotective effects, maintaining a basal level of normal autophagy in the myocardium during the subsequent exhaustive exercise [17]. This ability of the EP to activate autophagy processes helps to sense the cellular metabolic

Although in general, it is believed that preconditioning is directly triggered by a brief ischemia–reperfusion. It is known that brief ischemia produces transient dilatation (or stretching) of the heart. Therefore, it has been postulated that the stretching of the myocardium may be responsible for preconditioning, through the ion channels activated by stretching [18]. This idea can be supported indirectly by the fact that in chronic exercise, by increasing endothelial shear stress, increases NO production and ECNOS gene expression and can contribute to the beneficial effects of exercise in the cardiovascular system (ie say, antihypertensive) [19]. Although, as mentioned above, to say that the protective effect of preconditioning is due to a particular mechanism and not to a complex process, it is risky and simplistic.

The beneficial role of exercise on the cardiovascular system inevitably involves the regulation of vasodilation and vasoconstriction. In this sense, in stable coronary artery disease (CAD), exercise has been used as a treatment due to its endotheliumdependent vasodilator capacity, induced by acetylcholine. The molecular mechanism involved is through the phosphorylation of the eNOS-induced for Akt pathway [9]. This study demonstrates the role of exercise as a therapy in cardiovascular diseases, its actual use in therapy and the mechanism of action involved. To the extent that EP protocols are standardized and establish molecular relationships between the preconditioning processes, progress may be made in the non-pharmacological and/or combined treatment (drugs and exercise) of cardiovascular diseases.

Not only has it been linked to EP for the treatment of cardiovascular diseases, but it has also been shown to be useful for the treatment of doxorubicin poisoning (DOX), where it has been described that 2 weeks of EP are sufficient to prevent cardiorespiratory dysfunction associated with DOX and prevent mitochondrial

which prevents its progression. In this sense, recently, PE has been reported to attenuate pathological cardiac hypertrophy by increasing the functional capacity of the cardiovascular system, through the MAPK pathway [16]. Probably this protective effect is related to the systemic increase of ROS, one of the main stimuli that

the mechanisms by which this happens has not yet been elucidated.

processes, thus maintaining the homeostasis of cardiomycites.

**30**

Skeletal muscle represents one of the most abundant tissues of the organism, for many years its mechanical and structural role has been studied, without studying its role in the regulation and maintenance of energy metabolism, release of humoral factors, regulation of oxidative stress, among others. Physical exercise represents the participation of the cardiovascular, respiratory and naturally skeletal muscle systems. For this reason, it is not to be expected that the protective role of the EP will positively impact the skeletal tissue. The mechanisms involved in the production of the beneficial effects of preconditioning in skeletal muscle are not yet clear, although it has recently been shown to decrease skeletal muscle atrophy induced by the discharge of the hind limbs (HU) and the mechanism that can participate it is through HDAC4/Gadd45α [23]. Although, interestingly, the mechanisms of physical training to reduce muscle atrophy are associated with the biogenesis, function and redox balance of mitochondria, the same mechanism involved in preconditioning [24]. The redox mechanism seems to be common in preconditioning processes regardless of white tissue, probably not the only shared mechanism, but certainly unlike the cardiac muscle, in skeletal muscle hypertrophy represents a greater capacity for energy regulation.

On the other hand, the mechanisms involved in changes in the markers of muscle damage and the parameters associated with running economy (ER) are not related, that is, increasing the tissue damage in skeletal muscle does not improve the ER [25]. However, it is likely that in order to represent an improvement in the ER, a chronic protocol must be performed.

EP decreases arterial circulation in skeletal muscle, this confers hypoxia in the tissue. It has been reported that hypoxic preconditioning (HPC) can protect the function of respiratory skeletal muscle during reoxygenation through signaling cascades sensitive to redox mechanisms and the regulation of mitochondrial channels [26].

The protective effect of EP on skeletal muscle can be used for the treatment of muscular atrophy and strengthening of muscle tissue. It is still necessary to study the mechanisms that can contribute to improve it and optimize the protocols that are adapted to the physiological needs of patients.

On the other hand, preconditioning reduces the fatigue associated with repeated exercise speed [27], however, it is still necessary to establish exercise protocols

where the variables to be studied are identified and correlated with an increase in physical performance and/or increase of the ER.
