Mechanisms of exercise-induced health benefits

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Mechanisms of exercise-induced health benefits

-

A systematic review

by:

Marie Dahl Stangebye

Supervised by:

Tone Bere (PT, PhD) and Prof. Olav Røise (MD)

Project thesis, Faculty of Medicine University of Oslo

2019

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Copyright Author

Year: 2019

Title: Mechanisms of exercise-induced health benefits

Author: Marie Dahl Stangebye

http://www.duo.uio.no

Print: Reprosentralen, Universitetet i Oslo

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Abstract

BACKGROUND: It is well-known that physical activity is good for us. Although the skeletal muscle is the main organ which is directly affected, it has been shown that exercise can affect almost all organs and tissues in the body. The molecular mechanisms and signalling pathways responsible for these beneficial effects, both locally in the skeletal muscle and more peripheral, are gradually becoming known to us through extensive research. This allows us to better understand the way exercise affects our bodies, which might make it easier for physicians to prescribe it as a therapy equally and even more beneficial than drugs regarding effect and risk profile. It might also make it possible to pharmacologically target these pathways, raising the question of an “exercise-pill”.

OBJECTIVE: The aim of this thesis is to review the current literature on the molecular mechanisms of exercise-induced health benefits.

METHOD: Relevant literature was found in Medline and Embase. In addition, some articles were collected from references, and some were found coincidentally. Some information was also found in books on the subject.

RESULT: The available research describes several signalling pathways, and both epigenetics and the secretory function of the skeletal muscle is put forward as potential mediators of systemic exercise-induced health benefits. Exercise stimulates the skeletal muscle to produce and secrete several factors called myokines, and they mediate the effects of physical activity throughout the body. Our epigenome is also altered in response to exercise, providing a favourable epigenetic pattern in our genome.

CONCLUSION: Physical activity is extremely effective both in the prevention and treatment of several common diseases. Extensive research over the past decades have provided new insight on the molecular mechanisms governing the beneficial health effects of physical activity and exercise. This raises the possibility of pharmaceutical interventions targeting these signalling pathways, but it is unlikely that physical activity can be replaced by any one pill, and resources should be focused on implementing exercise in therapy as well as promoting a more active lifestyle on a population-scale.

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Sammendrag

BAKGRUNN: Det er et velkjent faktum at fysisk aktivitet er bra for oss. Selv om skjelettmuskelen er det direkte målorganet når vi trener, har det blitt vist at trening også påvirker flere andre organer og vev i kroppen. De molekylære mekanismene og signalveiene som står bak de positive helseeffektene, både lokalt i skjelettmuskelen og mer perifert, blir gradvis bedre kjent for oss gjennom grundig basalforskning. Dette gir ny innsikt i hvordan trening påvirker kroppen, noe som kan gjøre det lettere for leger å bruke trening som behandling som er minst like god som medisiner når det kommer til effekt- og risikoprofil.

Det kan også åpne for muligheten for medikamentell påvirkning av kjente signalveier.

OBJEKTIV: Målet med denne oppgaven er å samle oppdatert kunnskap om de molekylære mekanismene bak treningsinduserte helseeffekter.

METODE: Relevant litteratur ble funnet ved et systematisk søk i Medline og Embase. Noen artikler ble også funnet utenfor dette søket, og relevant stoff ble hentet fra bøker om fysisk aktivitet og helse.

RESULTAT: Tilgjengelig litteratur beskriver flere sentrale signalveier, og både epigenetikk og skjelettmuskelens sekretoriske funksjon ble trukket fram som potensielle mellomledd i veien til systemiske helseeffekter. Trening stimulerer skjelettmusklene til å produsere og sekrere en rekke faktorer som kalles myokiner, og disse medierer effektene av trening til hele kroppen. Epigenomet vårt endres også når vi trener, og dette gir genomet vårt et gunstig epigenetisk mønster.

KONKLUSJON: Fysisk aktivitet er ekstremt effektivt både i forebygging og behandling av flere vanlige sykdommer. Grundig forskning de siste tiårene har gitt ny innsikt i de

molekylære mekanismene som står bak de gunstige helseeffektene som kommer av fysisk aktivitet og trening. Dette åpner for muligheter innen farmakologisk intervensjon som etterlikner effekten av fysisk aktivitet. Det er likevel usannsynlig at trening noensinne kan erstattes av en enkelt pille, og ressurser burde derfor brukes til å implementere fysisk aktivitet i terapi, og til å skape et mer aktivt samfunn.

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1.Abbreviations

NCDs Non-communicable diseases METs Metabolic equivalents WHO World Health Organization

COPD Chronic obstructive pulmonary disorder RCT Randomised controlled trial

ROS Reactive oxygen species AMPK AMP-activated protein kinase MAPK Mitogen activated protein kinase PKC Protein kinase C

mTORC Mammalian target of rapamycin

S6K P70-S6K

NF-kB Nuclear factor kB

PGC-1 Perixosome proliferator-activated gamma coactiator 1 PPAR Perixosome proliferator-activated receptor

HSF Heat shock factor HIF Heat induced factor

MnSOD Mitochondrial superoxide dismutase GPX Glutathione peroxidase

GCS g-glutamylcysteine synthase VEGF Vascular endothelial growth factor JNK c-jun NH2 terminus kinase

ERK Extracellular regulatory kinase BDNF Brain derived neurotrophic factor

REDD-1 Regulated in development and DNA damage SPARC Secreted protein acidic and rich in cysteine SOD Superoxide dismutase

Hsp Heat shock protein

HDL High-density lipoprotein cholesterol LDL Low-density lipoprotein cholesterol IGF-1 Insulin-like growth factor 1

TNF-a Tumor necrosis factor alpha CRP C-reactive protein

ACF Aberrant crypti foci BMD Bone mineral density

AICAR 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside

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2. Introduction

Physical activity has been shown to be effective both in the prevention and treatment of a number of noncommunicable diseases (NCDs) like cardiovascular disease, diabetes and cancer (1). It also reduces the incidence of risk factors for these diseases, like hypertension and overweight/obesity. People undertaking regular physical activity will also experience improved mental health, quality of life and general well-being (2). These effects are so profound that it has been suggested that exercise can actually be considered as a drug (3), rivalling the effect of several drugs prescribed for e.g. diabetes, osteoporosis, cardiovascular disease and psychiatric disorders (4). Still, exercise as a treatment, is relatively little used in clinical practice, where physicians generally tend to use more conventional drugs or surgery.

This might be because of limited knowledge about how exactly physical activity affects the body on a molecular level, or because it is harder to motivate patients for this kind of treatment. The molecular mechanisms behind these beneficial health effects are now gradually becoming known, and this raises the question of exercise mimetics. This thesis provides a systematic review of this field, with the main focus on the mechanisms behind the health benefits exercise.

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3. Background

3.1 Physical activity in a historical perspective

Humans have evolved as endurance runners. Even though today it is primarily a form of recreation and exercise, evidence strongly suggests that it has roots as far back as the origin of the human genus (5). It is likely that individuals who were physically fit were at an advantage when it came to hunting and gathering, making them more likely to survive than their inactive or less physically able peers. In this way, according to Darwinian theory, evolution favoured the more active of the human species, and physical activity became a necessity to our health and survival (6).

From tomb drawings we know that physical activity was important even in early eastern civilizations. We have records of organized exercise for health promotion as far back as 2500 BC in China (7). Later, Hippocrates (460-370 BC), known as the ”father of Western medicine”, saw the importance of prescribing exercise for health-related benefits. He stated that “walking is man’s best medicine” and that “if there is a deficiency in food and exercise the body will fall sick” (8). We also know that Plato (427-347 BC) said: ”Lack of activity destroys the good condition of every human being, while movement and methodical physical exercise save it and preserve it” (9). The Greeks believed in physical well-being, fitness and a healthy, active lifestyle, and physical activity was an integral part of education (7).

Exercise used to be an essential part of daily life, necessary for survival. Today, most humans live in an environment where this is no longer the case. As a result, we are experiencing higher incidence levels of so called ”lifestyle diseases” like cardiovascular disease, diabetes and obesity, as well as some psychiatric and neurodegenerative disorders (10).

3.2 Definition of physical activity and exercise

Today, physical activity is defined as any bodily movement produced by skeletal muscle that requires energy expenditure, while exercise is defined as ”a subset of physical activity that is characterized as a planned and purposeful training” (11). However, the terms physical activity and exercise are often used interchangeably. Physical activity can take many forms, from recreational activities to tasks performed at work or in the home. Exactly what you do is not as important as the duration and intensity of the activity (2). We generally divide exercise into endurance and resistance exercise. When we undergo endurance exercise, we increase

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the aerobic capacity of the muscle cells, and they switch from a glycolytic to an oxidative phenotype. Resistance exercise induces hypertrophy and muscle strength.

Sedentary behaviour can be defined as any waking behaviour characterized by an energy expenditure £ 1,5 metabolic equivalents (METs) (12). This is equivalent to activities like sitting, reclining or lying down. Reducing this sedentary behaviour by even small periods of standing, walking or climbing stairs can help people towards achieving the recommended levels of physical activity for optimal health (2).

According to the global recommendations on physical activity from the World Health Organization (2010), adults aged 18-64 years should do at least 150 minutes of moderate- intensity aerobic exercise per week, or 75 minutes of vigorous-intensity activity (or a combination of the two). In addition, muscle strengthening activities should be done at least twice a week. Estimates from 2010 suggest that as many as 23% of adults and 81% of adolescents (11-17 years old) do not reach the recommended levels of physical activity. This accounts for huge costs to health systems and society, and could easily have been prevented (1).

WHO has identified physical inactivity as the fourth leading risk factor for mortality globally, which means 5,5% of all deaths. This makes physical inactivity a close second to tobacco use, which accounts for 8,7% of global mortality (13). Thus, WHO has now launched a global action plan called ”more active people for a healthier world”, with the goal being a 15% relative reduction in the global prevalence of physical inactivity in adults and adolescents by 2030. The aim of the action plan is to integrate physical activity into settings where people live, work and play, thereby making it more accessible. This requires a system based approach, which the action plan sets out to offer through 20 policy actions that are supposed to be universally applicable to all countries. By making people more physically active, we can reduce one of the leading risk factors for global morbidity and mortality, and reduce significant costs to society (2).

3.3 The health effects of exercise

Several studies have shown us that physical activity is effective both in prevention and treatment of many common chronic diseases (14). It protects us against cardiovascular disease, chronic obstructive pulmonary disease, obesity, type 2 diabetes, cancer, and several diseases of the joints and the musculoskeletal system, like osteoarthritis, rheumatoid arthritis, osteoporosis and fibromyalgia (14, 15). Increasing amounts of evidence also suggests that

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exercise acts as a potent psychoactive drug, improving cognitive function and protecting against psychiatric disorders like depression and anxiety (3, 6, 16).

Whereas the studies investigating the role of physical activity in primary prevention of these disorders are mainly observational, many of the studies in the field of secondary prevention are RCTs (14). These are the ones that can actually measure how effective the exercise therapy is compared to other kinds of interventions in specific patient populations (17), and therefore they are important if physical activity is to be implemented in the guidelines as an evidence-based non-invasive treatment.

Resistance exercise is very important in the prevention and treatment of diseases of the musculoskeletal system, like loss of muscle function and osteoporosis (18). It is also associated with better glycaemic control than endurance exercise alone (19). Though many of the health benefits related to cardiovascular disease are thought to be attributed to endurance exercise, several trials now suggest that a combination of endurance and resistance exercise are as good, or better, for the reduction of cardiovascular risk factors (20). This is reflected in the WHO recommendations from 2010 (1).

3.4 The dose-response relation

Some might think that the levels of activity needed to produce a health benefit are too hard to achieve for regular people with regular jobs. The uplifting news is that this is not the case. A study from 2004 showed that as little as an increase in weekly energy expenditure of 1000kcal (equivalent to 1 MET increase in physical fitness) results in a 20% reduction in mortality (21). This is approximately equal to walking at a fast pace for 25 minutes, 5 times a week (22) and should be reasonably easy for the majority of the population to accomplish, either as a planned activity, or in the form of spontaneous bouts of activity during a regular day (e.g. climbing stairs, walking or riding a bicycle to work, etc.). This is the same as the global recommendations from WHO for adults aged 18-64 years (see above). Some studies suggest that even lower levels of activity might convey beneficial effects (14, 23). Reducing sedentary time is by itself also associated with a significant reduction in all-cause mortality (24). This is important, because there is often too much focus on the “optimal” activity levels needed for good health, and this might discourage sedentary people from attempting to become more active.

Beyond this minimal level of physical activity needed to have an effect, we know that there is a dose-response relation between the amount of exercise and health benefits (25, 26).

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Although this relation might be different for different health outcomes (27), the message is clear: the more, the better. For centuries, it has been believed that vigorous and exhaustive exercise might be harmful, and this is still a subject of debate (28). Although more research is required to settle this debate for good, several studies show that elite athletes have an increased life expectancy (28, 29). Elite athletes of both aerobic and mixed aerobic and anaerobic sports survive longer compared to the general population. Whereas the results concerning elite athletes of power sports (anaerobic) are inconsistent, the results of analysing elite athletes of various sports together show that their mortality is generally lower than that of the general population (29). Therefore, health professionals and physicians should not be afraid to recommend strenuous exercise or high-level aerobic sports (3). As with many drugs used for pharmacological treatment, the dose of exercise can be titrated up from the minimal effective dose, until the desired effect is achieved (30).

3.5 Contraindications

Based on the available knowledge today, there are some conditions where physical exercise should not be recommended. They include coronary heart disease unless it has been stable for a least 5 days, dyspnea at rest, aortic stenosis, pericarditis, myocarditis, endocarditis, fever and severe hypertension (15). All of these conditions increase the work load of the heart, and any additional strain would be harmful rather than beneficial. Exercise should also be avoided in cases of acute joint inflammation, if the pain worsens after activity, and in cases with pleuritis (15). Osteoporotic patients should be encouraged to take part in strength training, but the activity should have a low risk of falling, as any trauma may easily lead to fractures (15).

Cancer is not a contraindication to exercise, and neither is ongoing radio- or chemotherapy unless leukocytes, haemoglobin or thrombocytes fall beneath a certain level (15).

Diabetic patients should avoid exercise if they have an ongoing episode of hypo- or hyperglycaemia, and patients with active proliferative retinopathy should avoid high-intensity training and exercises including Vasalva-like manoeuvres to prevent retinal bleedings due to the increased blood pressure. If the patient has neuropathy and/or incipient foot ulcers, exercises where they have to bear their own body-weight should be avoided in order to prevent further damage (15).

Some of the conditions mentioned above have a chronic clinical picture, making physical activity impossible for longer periods of time, whereas some are more transient, like fever,

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and is a hindrance only for a few days. In addition, people suffering from neurological disorders or paralysis of varying severity might find it difficult, or even impossible, to exercise. For people in these groups, it would be beneficial to have drugs mimicking the health effects of physical activity.

3.6 Future perspective – the “exercise-pill”

As stated above, the beneficial health effects of exercise in the general population are so pronounced that it has been proposed that exercise might actually be considered as a drug (3).

Imagine if you could get a pill from your doctor that would help prevent and cure several diseases which today contribute to the majority of all morbidity and mortality worldwide.

Furthermore, there are almost no adverse effects, and almost no contraindications. Would you take it? Most likely, the answer for the majority of us would be ”yes”. Still, many people find it hard to get enough physical activity in their daily lives.

Today, more research is focusing on the molecular mechanisms of the health benefits of exercise, increasing our knowledge about how exactly physical activity affects the body on a molecular level. This raises the question of exercise mimetics, or an ”exercise-pill”. The signaling pathways within the skeletal muscle has been thoroughly studied, and they are important for understanding both the local and systemic changes brought on by physical activity. The effect of regular exercise for health promotion and management of disease is well established, often proving equal to, or better, than drugs traditionally used in management and treatment. In this way, exercise can be compared to a drug, and the physiological changes taking place in our bodies are the pharmacodynamics of exercise.

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4. Objective

The aim of this thesis is to review the current literature on the molecular mechanisms of exercise-induced health benefits. I will provide an overview of the possible exercise-induced signaling pathways, and how they affect cells and tissues both locally and peripherally.

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5. Methods

The following search was executed in Medline and Embase in October 2018, and again in January 2019:

((exp Exercise) or (exp Exercise Therapy) or (exercise.tw,kf) or (physical activit*.tw,kf.)) and

((exp Reactive Oxygen Species) or (mechanism*.ti) or (exp Molecular Biology) or (molecular*.tw,kf) or ((exp Cell Death/ or cell death).tw,kf) or (exp Signal Transduction) or (exp Immunomodulation) or ((immune or immune).tw,kf) or (exp “Receptors, Cytoplasmic and Nuclear”) or (PPAR.tw,kf) or (PGC-1*.tw,kf) or (exp Interleukins) or (myokine*.tw,kf) or (exp Cytokines) or ((Brain-Derived Neurotrophic Factor/ or BDNF).tw,kf) or ((exp Vascular Endothelial Growth Factors/ or VEGF).tw,kf)

and

(health adj3 (benefit* or effect*)).tw,kf.

The search was limited to articles in Norwegian, Swedish, Danish or English, and produced 419 results in Medline. The same search was executed in Embase, and excluding results from Medline left 49 results. Despite the limitations in the search some of these were duplicates.

The results were evaluated by title and abstract before reading the entire review/article. After having evaluated them in this way, I ended up including 36 articles from Medline and 4 from Embase (Figure 1).

In addition, some articles were found in the references, and two were found outside of the search in the databases. I also used the book “Sterk hjerne med aktiv kropp” and three articles mentioned there (Figure 1) (31).

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Figure 1: A schematic summary showing the process of the systematic search of included articles (n=88).

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6. Results

6.1 The roles of skeletal muscle

The main organ targeted by physical activity is the skeletal muscle. In non-obese humans, it is the largest organ in the body, taking 15-20% of cardiac output at rest and as much as 70- 85% during exercise (18, 32). It is important for postural retention and locomotion, and it also plays a role in energy consumption and production, which affects the energy metabolism of the whole body. Skeletal muscle also has a third function, which is to synthesize and secrete several factors in response to exercise. These factors, called ”myokines”, are thought to be one of the main mechanisms underlying the systemic beneficial health effects of physical activity (33-35). The myokines are secreted by the muscle cells, and they have both local and systemic effects. This explains how the beneficial health effects of physical activity can be mediated to cells and tissues throughout the body.

When we exercise, several signalling pathways are activated in the skeletal muscle, leading to both local adaptions and the secretion of myokines. But what is it about physical activity that makes the muscle cells react in this way?

6.2 Exercise-induced adaption in the skeletal muscle

The subunits of the skeletal muscle are the myocytes, also called the muscle fibres. There are different types of fibres, divided by different types of myosin and their ability to undergo oxidative phosphorylation. Type 1 fibres, also called “slow-twitch fibres” contain high levels of myoglobin, are dense with capillaries, have many mitochondria and can utilise triglycerides as fuel. They are important for endurance, whereas type 2, or “fast-twitch”, fibres are responsible for increased power production. Type 2 fibres are divided into a continuum of subtypes, IIa, IIx and IIb, with an increasing amount of fast twitch myosin, power production, capillary density, oxidative capacity and resistance to fatigue (from a to x to b). The distribution of the different fibre types varies both between individuals, and between different muscles in one person (36).

All skeletal muscles have all the fibre types, but the composition varies with the role of the muscle and with activity. The adaption of the skeletal muscle is essential for the exercise- induced health benefits, both because of its importance in energy metabolism and its role as an endocrine organ (Figure 2). When we undergo endurance exercise, the fibres undergo a fast-to-slow switch, and the muscle becomes more oxidative than glycolytic. This means that

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the ability of the muscle to utilize oxygen in energy metabolism increases and this makes it able to endure longer bouts of exercise. Glycolytic muscle fibres, mainly responsible for increased power production, have a greater ability to utilize the glycogen stores in the muscle under anaerobic conditions. In response to resistance exercise, the main effect is increased production of muscle proteins and hypertrophy, without a change in muscle phenotype. The specific adaptions occur because different forms of exercise activate different signalling pathways in the myocytes, leading to both local adaptions and the secretion of myokines. The oxidative switch is mainly dependent on the AMPK- PGC-1a pathway, whereas muscle hypertrophy is the result of an activated PKB-TSC2-mTOR cascade (these signalling pathways are described in more detail below) (37). It would seem that the switch to a more oxidative phenotype is beneficial for the secretory function of the muscle (38), but the increased muscle strength and size brought on by resistance exercise is in itself important in many ways. It is important both for metabolism and glucose-homeostasis, and in the prevention of age-related atrophy and many muscle pathologies, which often hinders elderly people from activity and independence.

Physical exercise also promotes mitochondrial autophagy in skeletal muscle, which is essential in maintaining mitochondrial quality. This effect is mainly mediated by the AMPK- PGC-1a pathway (39). The increased expression and translocation of the insulin- dependent glucose transporter GLUT4 in the skeletal muscle increases the uptake of glucose from the bloodstream, and together with an increased insulin sensitivity this leads to an improved regulation of blood-glucose (40).

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Figure 2: Exercise induced adaptions in the skeletal muscle.

6.3 The signalling pathways

The contracting muscle cells are exposed to a number of chemical and mechanical stimuli, triggering a response that leads to an alteration in cellular function. There is an intracellular change in pH and metabolite concentration, a shift in the ATP-to-ADP ratio because of increased energy expenditure, a change in intracellular [Ca²⁺], increased production of reactive oxygen species (ROS), decreased intracellular pO2 (hypoxia),and mechanical force (stretch) produced by the contraction of the muscle fibres (3, 41, 42) (Figure 3). The contraction of the skeletal muscle is the first step, or the trigger, generating the changes in the intracellular milieu mentioned above representing the second steps in the signalling pathways ultimately leading to local cellular adaption and systemic health benefits. It is noteworthy that ROS are an important stimulus for several of these pathways, and that antioxidant supplements combined with physical activity inhibit several exercise-dependent signalling cascades. This happens because antioxidants decrease the levels of ROS, and the downstream targets in the signalling pathway will not be activated as strongly (3, 43-46).

Exercise- induced adaptions in

the skeletal muscle Switch in fibre

phenotype

Hypertrophy

Promotion of mitochondrial

autophagy

Increased aerobic capacity Increased

strength Increased GLUT4 on the

cell surface

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The factors mentioned above serve as the cellular “sensors” of exercise. They activate a set of kinases and phosphatases, which make up the next step in the exercise-dependent signalling cascade. Kinases are enzymes with the ability to add a phosphate group to a protein, and a phosphatase does the opposite. Generally, the addition of a phosphate group will activate the protein, whereas it’s removal will act inhibitory. This means that the kinases and phosphatases are responsible for activating or inhibiting a set of downstream proteins in the signalling cascade initiated by physical activity. They include AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), protein kinase C (PKC), Akt, the mammalian target of rapamycin 1 (mTORC1), p70S6K (S6K), calcineurin and Ca²+/calmodulin kinase. These activate a set of proteins called transcription-factors and co- activators, like NF-kB, p53, PGC-1, HSFs and hypoxia-inducible factor (HIF-1), which alters the expression of certain genes (40, 41, 47-49), mainly through the activation of proteins with deacetylase-activity called sirtuins (50). The transcription-factors work by binding to specific DNA sequences, thus regulating the expression of certain genes. The co-activators are yet another regulatory step, and they bind to the transcription-factors to enhance their activity.

Some of the activated genes lead to local adaption in the skeletal muscle, while others code for proteins which are secreted into the bloodstream as myokines (this will be discussed later).

Some of the signalling pathways have been more thoroughly studied than others. The ROS are important triggers for several of the signalling pathways, and the MAPK and AMPK pathways are two of the signalling cascades we know most about. Thus, these factors are described in more detail below.

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Figure 3: A summary of the signalling pathways regulated by exercise in skeletal muscle.

6.3.1. ROS

When we exercise, the skeletal muscle and myocardium will have an increased metabolic rate and oxygen consumption. This leads to an increase in the production of ROS, which are harmful compounds because they lead to oxidative damage in the cells. Conversely, it has been shown that animals exposed to chronic training show less oxidative damage despite the increased production of ROS, and this has been contributed to the upregulation of endogenous antioxidant enzymes like mitochondrial superoxide dismutase (MnSOD), glutathione peroxidase (GPX) and g-glutamylcysteine synthase (GCS). ROS seem to mediate this effect through activation of several downstream targets, like the transcription-factor called nuclear factor kB (NF-kB), which is transferred from the cytoplasm into the nucleus when it is activated. Once it is in the nucleus, it binds to its target genes, inducing the transcription of MnSOD, GPX and GCS (44). These endogenous antioxidants protect the cells from oxidative damage. This is an important adaption to chronic exercise, and the beneficial effect seems to be lessened when exercise is combined with antioxidant

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supplements, because they decrease the amount of ROS responsible for these adaptive changes (43-46, 51).

ROS also activates several other enzymes and transcription-factors, like MAPK, HIF-1 and AMPK (51). The transcription of e.g. vascular endothelial growth factor (VEGF) is upregulated by several factors, including HIF-1, and this leads to increased angiogenesis in response to exercise-induced hypoxia (50, 52).

6.3.2 MAPK-pathways

We know from studies that there are at least three distinct subgroups of mitogen-activated protein kinase (MAPK) that are activated in response to exercise; c-jun NH2 terminus kinase (JNK), p38 kinase and extracellular regulatory kinase (ERK). The activation of these pathways ultimately lead to transcriptional activation, affecting processes like carbohydrate metabolism, inflammation, apoptosis, cell differentiation and hypertrophy (41, 47).

6.3.3 AMPK, mTORC1 and Sestrins

The AMP-activated protein kinase (AMPK) senses energy depletion in the cell, and activates catabolic processes while inhibiting anabolic reactions (40). It is essential for acute exercise- induced autophagy in skeletal muscle, a process that seems to contribute to the beneficial metabolic effects of physical activity (49, 53). It is regulated by intracellular levels of cAMP and Ca²⁺, which activates Ca²⁺/calmodulin-kinase, making AMPK phosphorylated and active (54). When AMPK is activated, it works as an upstream regulator of the peroxiosome proliferator-activated gamma coactivator 1-alpha (PGC-1a) which stimulates the peroxisome proliferator-activated receptor (PPAR). In addition, PGC-1a recruits and co-regulates a number of other transcription-factors which activates nuclear-encoded mitochondrial genes, and is important for the regulation of mitochondrial biogenesis, autophagy, angiogenesis and oxidative metabolism. (4, 40, 42, 49, 53, 54). It also regulates the expression and translocation of the glucose transporter GLUT4 to the plasma membrane, leading to increased glucose uptake. These processes promote metabolic health, and secures the energy supply of the cell during physical activity. It is also important for glucose homeostasis both during exercise and under resting conditions (40).

The role of PGC-1a in exercise capacity, muscle function, oxidative metabolism and glucose homeostasis has been shown in several studies, proving its importance in the prevention of metabolic disease (53, 55-57). Recent studies also show that the activation of AMPK and

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PGC-1a in skeletal muscle can modulate the pathogenesis of some neurodegenerative disorders, like Huntington’s disease (58) Orally active AMPK-agonists could mimic some of these effects (discussed below).

The mammalian target of rapamycin 1 (mTORC1) can be thought of as a counterpart to AMPK, and they respond in a reciprocal manner to stimuli such as nutrition status and cellular stress (Figure 4). Whereas AMPK responds to energy depletion, and is activated during fasting and exercise, mTORC1 is chronically activated in response to hypernutrition.

It contributes to obesity-associated complications via its downstream targets, including the kinases p70S6K (S6K) and Akt (49, 59). Sestrins, a stress-responsive protein family, have recently been identified as a possible intermediate involved in metabolism homeostasis, as they seem to be involved in the mTORC1-AMPK signalling pathways. The sestrin family in mammals is composed of three genes, called Sestrin1, Sestrin2 and Sestrin3. Concomitant ablation of Sestrin2 and Sestrin3 leads to mTORC1-S6K activation and spontaneous insulin resistance even in the absence of hypernutrition and obesity (60). Sestrins are also upregulated by exercise, and this makes them the potential regulators of the downstream processes linked to these pathways, like embryonal development, carcinogenesis, immunity, metabolism and neurodegenerative diseases (49). They could provide a potential target for drug treatment of metabolic diseases in the future.

Figure 4: The relation between environmental factors, activation of AMPK and mTORC1 signalling pathways and outcomes.

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6.4 Systemic effects – the role of myokines

The search for an “exercise-factor” has been the aim of much research, and the discovery of myokines and the secretory function of skeletal muscle was a huge leap in this direction.

Several hundred of these proteins have been identified (61-64) (Table 1).

Table 1: Some of the identified myokines, and their effects in the organs and tissues targeted (62, 65-67).

Several studies have been executed in an attempt to identify the proteins secreted from contracting skeletal muscle. It seems that the change in cytokine production and secretion induced by exercise are more prominent in oxidative muscle cells than glycolytic (38). This indicates that the fibre switch occurring in regularly exercised skeletal muscle is important for the secretion of myokines and systemic health benefits (Table 2).

A study from 2018, analysing the circulating proteome of both sedentary and aerobic exercise-trained young men and women, as well as healthy older men, revealed several proteomic ”modules” that were affected by the habitual exercise status of the individual.

Additionally, some modules seemed to be preserved in the older, exercising men, indicating that exercise might prevent an age-related change. These proteomic patterns included molecules that we know are related to biological pathways involved in wound healing, regulation of insulin and glucose, inflammatory/immune responses, cellular stress signalling and apoptosis. These patterns are also closely associated with clinical indicators of lifespan, such as diastolic blood pressure, insulin resistance, VO2max and vascular endothelial

Myokine Affected organs Function IL-6 Brain

Adipose tissue Liver

Glucose homeostasis during exercise.

Stimulation of lipolysis and lipid oxidation.

Anti-inflammatory effect IL-10 Immune system Anti-inflammatory effect.

IL-8 Neutrophils Increased chemotactic accuracy.

IL-15 Adipose tissue Skin

Modulation of adipose tissue deposition.

Counteracts structural deterioration.

BDNF VEGF IGF-1 Serotonin

Brain Increased neuronal plasticity and hypertrophy.

Angiogenesis.

Irisin Adipose tissue Browning of white adipose tissue.

SPARC Colon Suppression of colon tumorgenesis.

Myostatin Skeletal muscle Adipose tissue

Skeletal muscle repair.

Favourable adaption of adipose tissue.

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function (68). Several of the proteins identified in this study have already been indicated as potential mediators of exercise-related health benefits in other studies, like BDNF, IL-6, SPARC, decorin, Hsp60, Hsp70, SOD and IL-8 (34, 68-71).

Table 2: The systemic beneficial effects of exercise.

6.4.1 The heart and vasculature

The effect of physical activity on cardiovascular health is well documented in the literature (14, 15, 25, 72). It has a positive effect on several risk factors related to cardiovascular disease and all-cause mortality, including insulin resistance, hyperinsulinemia, hyperglycaemia, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL) and high low-density lipoprotein cholesterol (LDL). These factors usually go together with increased central adiposity and obesity, and is collectively called “the metabolic syndrome”.

Together with the chronic low-grade inflammation associated with overweight and obesity (discussed below), the high levels of glucose and lipids lead to increased atherosclerosis and poor endothelial function. This increases the risk of ischemic heart disease and stroke (73).

Long-term lifestyle interventions are very effective in the prevention and treatment of cardiovascular disease (74), and a recent study proved that shorter exercise regimes also sufficed to bring forth these beneficial effects (75). The effect seems to be, at least in part, independent of weight loss (72, 75).

Organ/pathology Beneficial effect Heart and

vasculature

Ø Reduced risk of coronary heart disease and stroke.

Ø Reduced atherosclerosis and better endothelial function.

Brain Ø Increased cognitive function and memory.

Ø Protection against neurological disorders like depression, anxiety and dementia.

Ø Protection against several neurodegenerative disorders.

Adipose tissue Ø Phenotype switch, resulting in increased thermogenesis, lipid oxidation and insulin sensitivity, and decreased secretion of pro-inflammatory cytokines.

The immune system

Ø Increased protection against infections.

Ø Reduced systemic inflammation.

Cancer Ø Reduced risk of colon and breast cancer.

Bone and joints Ø Increased bone mineral density and strength.

Ø Improvement of inflammatory joint diseases.

Skin Ø Attenuation of age-dependent structural deterioration.

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6.4.2 The brain

In recent years, the link between physical activity and the brain and nervous system has been exhaustively researched. It protects against several common neurological disorders, like dementia, anxiety and depression It is also useful in the treatment of these conditions (31, 76). Exercise also seems to play an important role in the modulation of several neurodegenerative disorders, like Huntington’s disease and multiple sclerosis (MS) (58, 77).

Several possible mechanisms for these effects have been postulated, and include increased neurotrophin production and signalling, increased angiogenesis and blood flow in the brain, the beneficial effect on inflammatory processes and epigenetic changes in specific parts of the brain (76). The main myokines that seem to be important in this aspect are BDNF, serotonin (5-HT), VEGF and Insulin-like Growth Factor 1 (IGF-1) (31, 78-80).

A study performed on rats showed that habitual aerobic exercise upregulated the expression of both serotonin and BDNF in the brain, and this was associated with more efficient cognitive behaviour. Exercise also seemed to inhibit the age-related decline in the BDNF-5- HT system and cognitive function (78). Another recent study performed on elderly women in Gdansk showed that regular walking exercise significantly improved cognitive function. This improvement was accompanied by a rise in serum levels of BDNF, irisin and IL-6, suggesting that these myokines could have mediated the effect (81).

The increase in IL-6, BDNF and VEGF in the brain during and after exercise is not only contributed to secretion from skeletal muscle, but also to increased expression in the brain itself (64, 82). Interestingly, the IL-6 secretion from the brain is diminished with hypoglycaemia, whereas the secretion from skeletal muscle is inhibited by glucose ingestion, suggesting that IL-6 derived from brain and skeletal muscle has different functions (64, 83).

The increased angiogenesis and expression of VEGF in the brain following strenuous exercise had been linked to the secretion of lactate from working skeletal muscle. Lactate activates the lactate receptor HCAR1, which is highly expressed in the vessels supplying the brain. Both high intensity exercise and subcutaneous injections with lactate resulted in increased levels of cerebral VEGF, but this was not seen in knockout mice lacking HCAR1.

This proves that HCAR1 is necessary for lactate to elicit the cerebral response (83).

In addition to the improvements in cognitive function following exercise, the effect can actually be measured physically. The hippocampal area, responsible for e.g. long-term memory, actually increases in size in response to exercise. One study, following 120

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participants for a year, showed that as little as 40 minutes of rapid walking three times a week was enough for hippocampal growth. The control group did yoga and stretching, which did not lead to an increased heart rate. The walking programme was enough to increase the size of the hippocampus with 2%, while the control-group, experienced an age-dependent shrinkage of around 1%. This proves that high-intensity exercise is not essential for the beneficial effect to occur (84).

As mentioned above, the beneficial effect of exercise on the brain can be acquired already before birth, if the mother exercises during pregnancy (85, 86).

6.4.3 Adipose tissue

White adipose tissue serves as an energy storage in humans, and it is well known that adipose tissue also produces and secretes several pro-inflammatory cytokines in response to inactivity, called adipokines. The inflammation in the adipose tissue is thought to be because of adipocyte hypertrophy, resulting in inadequate blood supply, hypoxia, cellular stress, necrosis and macrophage invasion (67, 87). This inflammation, driven mainly by the adipokines tumor necrosis factor a (TNF-a), and resistin, promotes the development of several metabolic disorders, like type 2 diabetes mellitus and atherosclerosis (65, 67). TNF-a is a direct inhibitor of insulin signalling, thus promoting insulin resistance (88). The production of TNF-a in adipose tissue results in elevated levels of soluble TNF-a receptors, IL-6, IL-1 receptor antagonist and C-reactive protein. It is important to note that even though adipose-tissue derived IL-6 seems to be pro-inflammatory, or merely a marker of inflammation, skeletal muscle derived IL-6 is produced via another pathway, and has been shown to have anti-inflammatory effects (67, 89). Recent studies suggest that some of the myokines released from contracting skeletal muscle interact with adipose tissue in a beneficial way. Among those identified are myostatin, irisin, IL-6 and IL-15, and they lead to a favourable switch in function and phenotype of the white adipose tissue. They result in increased thermogenesis, lipid oxidation and insulin sensitivity, and decreased inflammation (65, 90). Muscle derived IL-6 also seems to inhibit the production of TNF-a, thus improving insulin sensitivity (64, 67). The anti-inflammatory role of myokines will be discussed in more detail below.

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6.4.4 The immune system Infections

It has been a common misconception that physical exercise induces inflammation and promotes a temporary immunosuppressive effect. This was supported by studies suggesting an “open window” hypothesis, because the levels of peripheral blood immune cells were shown to be transiently decreased in the hours following vigorous exercise. It was natural to suppose that this led to an increased risk of infection. Levels of salivary IgA were also lowered, indicating an increased risk of opportunistic infections. However, from the end of the twentieth century and onwards, several studies were executed in order to determine whether or not infection incidence is increased in athletes (both elite and recreational) following vigorous exercise. It was established that the transient decrease in blood immune cells was due to redeployment into peripheral tissues, thus improving immune surveillance.

Another finding was that the secretory rate of salivary IgA was increased following exercise, even though salivary flow was reduced, thus improving the quality even though the quantity is reduced.

Several recent studies have also shown that the function of neutrophils and monocytes is improved with habitual physical activity (91, 92). This could be due to epigenetic changes, as discussed above (93). Epidemiological studies show that leading an active lifestyle protects against both communicable and non-communicable diseases, suggesting an improved immune function as a result of exercise (94).

As mentioned above, research articles published in more recent years supports the suggestion of an exercise-induced improvement of the immune system. A study on obese and non-obese mice showed that exercise was accompanied by decreased disease severity when they were subjected to a viral influenza infection, although the mechanisms governing these effects were different. This shows that the beneficial immunological effect of exercise is independent of weight loss (95).

Sterile inflammation

The immune system is a key factor in the pathogenesis of several chronic diseases, as many of them are associated with low-grade systemic inflammation. This includes cardiovascular diseases, type 2 diabetes, some types of cancer and dementia (62, 67). As mentioned above, adipose tissue induces inflammation through the secretion of pro-inflammatory cytokines like TNF-a and C-reactive protein (CRP). The levels of CRP were also elevated the day after

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prolonged physical exercise, supporting the belief that vigorous exercise promotes inflammation (89). Recent studies have shown that exercise actually has an anti- inflammatory effect, and several researchers have sought to elucidate the mechanisms mediating this effect. Many of the myokines identified, especially IL-6, seem to be involved in the regulation of systemic inflammation, which in itself has been associated with a number of chronic diseases (65, 67, 89, 96). The elevation in CRP actually seems to induce an anti- inflammatory effect by promoting the induction of anti-inflammatory cytokines from circulating monocytes and by suppressing the synthesis of pro-inflammatory cytokines in tissue macrophages (67, 89). Epigenetic changes brought on by habitual exercise also seems to affect immune pathways in a favourable manner (93).

6.4.5 Cancer

Several epidemiological studies have shown the association between regular physical activity and carcinogenesis, especially decreased risk of breast and colon cancer (25, 97-100). Recent studies suggest that myokines might be responsible for this effect, at least in part. Other possible mechanisms through which exercise exerts cancer prevention is through its anti- inflammatory effect and the increased immune surveillance discussed above. Epigenetics might also play a role, and several studies have shown epigenetic alterations in genes related to cancer (101).

A recently discovered myokine, secreted protein acidic and rich in cysteine (SPARC), might play an important role in the prevention of colon cancer. It has already been shown that regular exercise prevents the formation of aberrant crypt foci (ACF), which are precursor lesions for colon adenocarcinoma, and SPARC might be the underlying factor mediating this effect (97). It is secreted from skeletal muscle in both mice and humans in response to exercise, and seems to inhibit colon tumorgenesis by increasing apoptosis. This effect was not seen in SPARC-null mice (66).

6.4.6 Bone and joints

The maintenance of skeletal health in adults is dependent on constant remodelling of the bone. The resorption is carried out by osteoclasts, and the formation by osteoblasts. The two processes are normally in perfect balance, and the amount of bone is kept constant. In response to some hormones and mechanical load, the balance can be shifted, promoting either resorption or formation, and the structure of the bone can be altered (102).

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Both aerobic and strength exercise can be beneficial for bone and joint health. Whereas patients with osteoarthritis mainly benefit from strength training, patients with rheumatoid arthritis or osteoporosis seem to benefit from both aerobic and weight bearing exercise (15).

The effects are probably mediated both through increased bone formation due to mechanical load, and through inhibition of inflammatory cytokines like TNF linked to e.g. rheumatoid arthritis (15).

Although weight bearing exercise, particularly resistance exercise, seems to have the greatest effect on bone health, some studies also provide evidence of the beneficial effect of endurance exercise (14). A study proving the effect of aerobic exercise on bone health found that medium intensity treadmill exercise increases bone mineral density (BMD) and bone strength in mice. These results were better than in the low intensity group. High intensity exercise maintained or even increased bone strength, although it had a negative effect on bone mass (103).

6.4.7 The skin

When we get older, our skin usually undergoes structural changes that lead to delayed healing, compromised barrier function and increased susceptibility to disease. A study done on mice from 2015 proved that exercise-induced IL-15 is important for the regulation of mitochondrial function in the skin, and that the activation of AMPK in skeletal muscle is essential for the rise in serum IL-15 after a bout of exercise. Daily intravenous injections of IL-15 attenuated the age-dependent structural change in skin and muscle, and the elimination of muscle AMPK was linked to both lower levels of serum IL-15 and structural deterioration of the skin. This suggests that IL-15 is a myokine which regulates skin metabolism (104).

6.5 Epigenetics

Several of the pathways mentioned above lead to an altered transcription pattern in the cells on a more permanent level, by changing the human epigenome. The epigenome is defined as all the chemical alterations of our DNA regulating its expression. The epigenome is more readily altered than the DNA itself, and is important in an evolutionary perspective. Whereas the DNA is changed by random mutations, and passed on to the next generation through natural selection, the epigenome can be altered by environmental factors that occur during a lifetime. The change in gene expression in the absence of an altered genotype is called epigenetics, which mainly occurs pre-transcriptionally through methylation of DNA and

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acetylation of histones, and post-transcriptionally via microRNAs (non-coding RNAs) (105).

Other non-coding RNAs are also upregulated by exercise, and might have a regulatory function on the signalling pathways responsible for exercise-induced health benefits (106).

The epigenome decides which genes are active or repressed, and can be regulated by environmental factors like exercise, nutrition and other stressors (105, 107-110). Epigenetic changes brought on by physical activity are now thought to play a role in the prevention and modulation of several diseases, like cancer and neurodegenerative disorders (82, 101).

Studies have shown that exercise can change genome-wide methylation patterns and gene expression, as well as in specific tissues (101). In one such study, long term endurance exercise in rats caused epigenetic changes in the skeletal muscle, preventing the development of disuse atrophy that usually comes with old age (110). The altered epigenome is also responsible for a shift both in muscle fibre type and in metabolic and secretory function (18).

Favourable epigenetic changes can be seen not only in the skeletal muscle, but also in the brain, blood-cells and other organs. In the brain, the genetic remodelling increases the production of factors that are known to improve learning and memory, like brain-derived neurotrophic factor (BDNF) (82, 93, 105). This explains how epigenetics might be one of the possible mechanisms for exercise-induced health benefits not only in the skeletal muscle, but throughout the body.

A meta-analysis from 2015, including 16 articles, identified several genetic loci in human skeletal muscle that were affected by exercise, and the methylation change seemed to be greater when the person exercising was older. Several of the affected genetic networks that identified in this study are important for cancer suppression (109).

Exactly how exercise is able to regulate the genome in this way is still not completely understood. One of the possible mechanisms suggested is dependent on a stress induced protein called REDD1 (Regulated in Development and DNA Damage 1), which shows a transient elevation in concentration after an exercise bout (111).

Several studies on exercise during pregnancy suggests that the epigenome of the child can be positively influenced already at this point (85, 86, 112). Although many of these studies are on rats, a research group in Canada were able to show that the same was true for humans.

Women who exercised for 20 minutes three times a week during pregnancy had babies with more mature brains than the babies in the control-group (85). Some studies even suggest that

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the epigenome of germ-cells can be altered by exercise, raising the possibility of trans- generational inheritability of cognition, health and disease risk (86, 108).

6.6 Gymnomimetics

In addition to providing new insight into the mechanisms by which physical activity affects the human body, this field of research opens up to the possibility of drugs mimicking the effect of exercise. Drugs that exert their effect by mimicking the effect of physical activity and exercise are named gymnomimetics. Given the wide range of health benefits that can be attributed to physical activity, such drugs could prove useful in the prevention and management of a number of diseases.

Although there are no drugs to date that can effectively mimic all of the beneficial effects of exercise, several compounds affecting some of the pathways mentioned above have been identified. Gymnomimetics can target any step in the signalling pathways described above. In theory, targeting an early step in the signalling cascades might elicit a broader response, whereas administration of any one myokine would possibly benefit a narrower selection of physiological processes.

5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), is an orally active AMPK- agonist, which seems to work as an exercise mimetic. It increases expression of the PGC-1a gene, and increases endurance even in sedentary mice (40, 113). Another possibility is manipulation of the transcription-factor PPAR. Oral administration of PPARd-agonists regulates skeletal muscle metabolism, increasing the amount of oxidative muscle fibres.

However, the PPARd-agonist GW1516 seems to only have an enhancing effect on exercise, and increases endurance only when combined with exercise training (113). PGC-1a itself has shown promise as a potential drug in the treatment of type 2 diabetes (56, 57). Although AMPK-activation seems to be important in the modulation of e.g. Huntington’s disease, the administration of AICAR to these patients may provide therapeutically relevant benefits, but showed no improvements in the hallmarks of the disease (114).

Other possible pharmaceutical targets are being discovered rapidly. Given what was recently discovered regarding the relation between lactate, HCAR1, cerebral VEGF and angiogenesis, it would seem that lactate or other HCAR1-agonists could protect against cognitive disorders associated with hypoperfusion. This could improve treatment of patients who are unable to undergo high-intensity exercise (83).

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Drugs targeting epigenetic factors are already being used in the treatment of several diseases, like cancer and epilepsy. Given the emerging knowledge about the epigenetic mechanisms governing exercise-related health benefits, this could be a possible target for intervention (101).

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7. Discussion

7.1 Mechanisms governing the health benefits of exercise

The results provided much information about possible signalling pathways governing the beneficial effects of physical activity on health. The skeletal muscle has been identified as an endocrine organ, and this function is enhanced through local adaptions that occur after exercise. Exercise and physical activity stimulate the muscle to produce and secrete several factors called myokines, and they act through autocrine, paracrine and endocrine pathways.

In this way, they are important for the systemic health effects caused by physical activity.

Another contributing factor is the change of the epigenetic pattern; studies reviewed in this thesis have shown that these exercise-induced epigenetic changes are favourable for our health.

7.2 Implementing physical activity in therapy

The prescription of exercise in therapy is not as easy as prescribing a pill. The patient compliance is generally low, in spite of the obvious health benefits, both mentally and physically. The problem lies in converting this knowledge and thoughts into action. As physical inactivity is now a major problem, the promotion of exercise and physical activity is a matter of public health.

Health care professionals are generally in a good position to motivate patients to lead a healthier lifestyle, but many physicians are reluctant to prescribe exercise in therapy. This could be contributed to lack of knowledge, both regarding the mechanisms of action and what modality, intensity and volume should be recommended. Some might even be scared to recommend exercise to patients with e.g. previous ischemic cardiac events or pregnant women. Steps need to be taken in order to counteract this hesitancy.

The publication of “Aktivitetshåndboka – fysisk aktivitet i forebygging og behandling” by the Norwegian Directorate of Health in 2017 was aimed at increasing competence among health care professionals regarding the use of physical activity in therapy (115). It provides a very specific plan of actions in relation to a number of common afflictions and diseases, as well as evidence of its efficacy. It will hopefully help physicians become more secure in the field of exercise therapy. After all, the adverse effects of exercise are very limited, often making it a much safer choice for first-line treatment than drugs.

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On a more individual level, some Norwegian physicians working in primary care have taken the initiative to start an exercise-group where they are physically active with their patients.

The project began in 2014, offering exercise two times a week (31). One physician and one physiotherapist were present each time. The patients were thoroughly examined before the first gathering and received close follow-up during the programme. The groups are not mandatory, but the physicians encourage the patients through reminding text-messages and low threshold activities. The results were exclusively positive – a healthier group of patients and a greatly reduced consumption of drugs. In the beginning, only one out of ten participants reported that they met the recommended levels of physical activity. Four years later, this number had increased to seven out of ten. The participants also reported a higher quality of life after the intervention, measured using a standardised questionnaire on physical, mental and cognitive health (31).

7.3 Gymnomimetics

The concept of an “exercise pill” has been thoroughly discussed in recent years. The search for an “exercise factor” has been going on for decades, and the discovery of myokines was a huge breakthrough in this field of research. Since many of the myokines have been thoroughly examined, we have come to know a lot about how they affect their target tissues, and several of them might possibly be used in the prevention and treatment of disease. As mentioned above, some of the signalling pathways may also be pharmacologically stimulated in the absence of physical activity.

However, it is unlikely that any one drug will ever be able to fully replace actual physical activity, and the fact remains that exercise is still the easiest and most efficient way to obtain all of the beneficial effects conveyed in this thesis. This highlights the importance of educating physicians in this field of therapy, and to successfully implement exercise therapy in more treatment regimes.

If we could create one or more drugs mimicking the effects of exercise, there would still be a number of ethical dilemmas to address before using them in therapy. One of the most important would be who it should be administered to. What would it mean for the future of our species if there suddenly existed a “quick fix” to sedentary lifestyle and inactivity?

Should it be given in order to enhance exercise performance? The answer to this would most likely be that it should be administered to patients who, for one reason or another, are unable to meet the required demands for physical activity. This would include patients with chronic

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contraindications, or who are more or less unable to move. But should it also include people who claim they can’t find the time for physical exercise because of work, children or other engagements? The limits would be hard to set in stone.

Some gymnomimetics, like AICAR and GW1516, are not only beneficial for health, but are able to increase endurance. Especially the PPARd-agonists (GW1516) are able to enhance the effect of exercise, and these drugs pose a potential problem in sports, where they can be used illegally.

There is also the question of whether or not it is ethically defendable to use resources in search of an exercise-pill, when actual physical activity is already proven to be extremely effective. As far as pharmaceuticals go, it is the perfect drug, providing prevention and management of a broad spectre of disorders while posing minimal threat of adverse effects.

The number needed to treat equals one. Knowing this, one might question whether the resources should be redistributed to the promotion of physical activity as part of a public health programme.

7.4 Methods

This thesis covers a very broad field of research, reflected in the number of search results.

Consequently, it was impossible to include all the relevant articles, and the study is potentially biased. On the other hand, because of the large amount of research conducted on several of the topics in this thesis, most of the results have been confirmed by many researchers independent of each other.

7.5 Conclusion

Physical activity is an effective therapy both in the prevention and treatment of several common diseases. Extensive research over the past decades have provided new insight on the molecular mechanisms governing the beneficial health effects of physical activity and exercise. This makes it easier to understand why and how exercise is so important for our health, and it also raises the possibility of pharmaceutical interventions targeting these signalling pathways. Although it is an intriguing notion, the fact remains that physical activity will never be replaced by any one pill, and resources should be focused on implementing exercise in therapy as well as promoting a more active lifestyle on a population-scale

Mechanisms of exercise-induced health benefits