1. Introduction
Physical exercise has been shown to be protective against cardiovascular diseases (CVD), the leading cause of death worldwide [
1]. Despite remarkable progress in medical, interventional, and surgical treatment options of CVD over the last years, prevention will be more and more vital for healthcare systems in an aging society. An alarming increase in the incidence of CVD-associated diseases such as insulin resistance, type II diabetes mellitus, and obesity demand altered lifestyle behaviors including dietary changes [
2], cessation of smoking [
3], and frequent physical exercise which all reduce risks for CVD clearly. The American Heart Association (AHA) therefore recommends at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous aerobic activity or a combination of both per week as well as a moderate- to high-intensity muscle-strengthening activity on at least 2 days per week [
4]. The beneficial effects on the cardiovascular system apply not only to young and healthy individuals [
5] but also to patients with distinct cardiovascular risk factors or overt CVD and seem to decline after detraining [
6,
7]. Most importantly, exercise seems to be protective against myocardial ischemia-reperfusion injury [
8].
Different acute and chronic changes in autonomic regulation, cardiac metabolism, signaling pathways, and protein expression in exercising hearts leading to cardiac growth and cellular reprogramming have been discovered over recent years. Especially, the beneficial effects of sports in heart failure and stable angina pectoris on patient outcomes, hospital admission, quality of life, and exercise capacity have been demonstrated [
9,
10,
11]. However, the exact mechanisms of how physical activity delays the development of cardiovascular diseases remain unclear.
Physiologically, the heart can adapt to chronic exercise in order to meet the enhanced oxygen demand of the body, a process called ‘remodeling’. Exercise above three hours per week results in a significantly lower resting heart rate as well as significantly higher maximum oxygen uptake (
O2) and left ventricular mass [
12]. Aerobic training thus promotes physiological cardiac hypertrophy and can contribute to a preserved cardiac function. This has high clinical impact as training can counteract declined cardiac function to a certain extent in injured as well as in aging hearts.
Physiological hypertrophy is initiated via humoral factors and mechanical stress leading to changes in intracellular cardiac signaling to affect gene transcription, protein translation and modification, and metabolism [
13]. These intracellular responses at a molecular level are different to those seen in pathological hypertrophy. In this context, exercise-modulated gene expression and cell signaling might protect the heart from further injuries and continuous maladaptive remodeling processes. Further understanding and identification of pathways responsible for physiologic exercise-induced adaption resulting in a cardioprotective phenotype with physiological hypertrophy and proliferation might help to identify triggers for physiologic/cardioprotective and pathologic/maladaptive remodeling that could potentially be used therapeutically to maintain cardiac function after ischemic or infectious injury of the heart as well as in aging hearts.
In the following review, we highlight these cellular mechanisms of cardiac remodeling in response to physical exercise with a focus on signaling pathways and microRNAs.
3. MicroRNAs
MicroRNAs are small noncoding RNA molecules of approximately 22 nucleotides in length modulating gene expression post-transcriptionally by binding to its target messenger RNAs promoting their degradation [
84]. Several animal and human studies have shown altered miR levels in cardiac diseases such as hypertrophy, ischemic, and dilated cardiomyopathy, aortic stenosis, or arrhythmias [
85,
86,
87,
88,
89,
90].
As described above cardiac cell regeneration was thought to be a rare event in adult mammalian hearts for a long time but recently different miRNA clusters have been linked to increased cardiomyocyte proliferation and cardiac regeneration whereas others have been related to reduced cardiomyocyte proliferation. Recently, however, animal studies revealed detailed insights in cardiac regeneration processes including cardiomyocyte proliferation in failing hearts [
91,
92] and inducible regeneration in adult cardiomyocytes [
16,
17,
18]. Renewal of adult cardiomyocytes after acute injury of the heart is therefore present yet insufficient [
93]. MicroRNAs are directly linked to control this cardiomyocyte regeneration, renewal, and proliferation. Many of these findings were obtained in exercise animal studies and may further contribute to develop novel innovative therapeutic strategies for patients with failing hearts in the future.
Table 1 gives an overview of cardiac microRNAs changes in response to physical activity.
Several microRNAs have been discovered contributing to an improved cardiac repair after distinct cardiac injury [
103]. Among those, the miR-17-92 cluster seems to play an important role in regulating cardiac growth, proliferation, hypertrophy, and survival in response to exercise [
94]. This microRNA family is known for regulatory influences on cell cycle, apoptosis and proliferation and has been linked to enhanced proliferation and survival of colorectal cancer [
104] as well as keratinocyte proliferation and metastasis [
105]. Shi et al. confirmed the role of miR-17-3p in cardiomyocyte hypertrophy and proliferation in a rodent model of exercise: Inhibition of miR-17-3p in mice decreased exercise-induced cardiac growth, cardiomyocyte hypertrophy and expression of markers of myocyte proliferation. Furthermore, mice treated with a miR-17-3p agomir received protection against cardiac remodeling after cardiac ischemia. The authors identified that miR-17-3p suppresses TIMP3, an inhibitor of EGFR/JNK/SP-1, a pathway promoting cardiomyocyte proliferation [
106], as well as PTEN which antagonizes PI3K/Akt pathway [
107], a pathway vital for cardiac hypertrophy [
58] as elucidated above. Samples of ventricular cardiomyocytes obtained in patients with dilated cardiomyopathy revealed a downregulation of miR-17-3p, which confirms its important role in cardiac remodeling, growth, and proliferation.
Exercise-induced activation of PI3K/AKT/mTOR signaling and subsequent left ventricular physiological hypertrophy is not only mediated via disrupted miR-17 levels but also via other miR-clusters as shown in a rat model [
63]: Ma et al. found decreased miRNA-124 levels (targeting PI3K) and increased miRNAs-21, -144, and -145 (targeting PTEN and TSC-2), all leading to an induced activation of PI3K/Akt/mTOR signaling in cardiomyocytes. Furthermore swimming exercise and application of recombinant human growth hormone (r-hGH) in rats altered cardiac PI3K/Akt/mTOR signaling and miR-21 and miR-133 expression [
96]. Reciprocal repression between miR-133 and calcineurin is involved in regulating cardiac hypertrophy [
98]. These findings emphasize the significance of PI3K/Akt signaling in cardiac proliferation and physiological hypertrophy and support the beneficial effects of physical activity.
Importantly, miR-222 was identified as a key regulator of exercise-induced cardiomyocyte growth and proliferation in mice as induced miR-222 expression in cardiomyocytes led to resistance against adverse cardiac remodeling and ventricular dysfunction after ischemia [
95]. These effects were mediated via inhibition of p27, Hipk1, and Hmbox1. Inhibition of endogenous miR-199a was shown to contribute to physiological cardiac hypertrophy probably due to the upregulation of PGC1α in treadmill-trained mice [
101]. In another promising study treatment with either miR-199a or miR-590 elevated cardiomyocyte proliferation in postnatal mice promoting cell-cycle re-entry, recovered cardiac contractility, and decreased the levels of fibrosis after myocardial infarction [
103].
In contrast miR-15 family attenuates heart regeneration through inhibition of postnatal cardiomyocyte proliferation and acute inhibition of miR-15 in adult mice is associated with improved contractile function after ischemic injury [
108].
Physical activity also leads to altered miR clusters affecting increased cardiac angiogenesis in animal models. Among those miR-15 is involved in controlling angiogenesis and downregulated under hypoxic conditions [
109]. Increased miRNA-126 expression is associated with exercise-induced cardiac angiogenesis in response to changes in vascular endothelial growth factor (VEGF) pathway as well as mitogen-activated protein kinase (MAPK) and PI3K/Akt/eNOS pathways in rats [
97]. Decline in cardiac microvascularization is a finding often obtained in aging and diabetes mellitus. Exercise training in this context attenuated aging-induced downregulation of VEGF signaling cascades including phosphorylation of Akt and eNOS proteins contributing to an improvement of angiogenesis in old age rats [
110].
Ventricular stiffness, increase in fibrosis and diastolic dysfunction often accompanies heart failure. MiR-29c was found to be involved in improving ventricular compliance: Exercising rats showed increased miRNA-29c expression correlating with a decrease in collagen I and III expression and improved LV compliance [
99]. Exercise-induced release of exosomes from cardiomyocytes containing miR-29b and miR-455 downregulated matrix metalloproteinase 9 (MMP9) resulting in decreased fibrosis and matrix degradation [
100].
Swimming-trained mice showed decreased cardiac apoptosis via increased Bcl-2/Bax ratio, an effect mediated via miR-1, miR-30b, and miR-21 [
102].
Changes in miRNA expression found in animal studies seem to be at least in part transferable to humans though their significance is still incompletely understood: Increases in circulating miR-126 have been also shown in healthy adults after endurance exercise [
111]. miR-1, miR-133a, and miR-206 levels were significantly elevated after exercise and correlated with performance parameters such as maximum oxygen uptake and anaerobic lactate threshold [
112].
4. Metabolic and Mitochondrial Cardiac Changes
Exercising cardiomyocytes predominantly use glucose and fatty acids to generate energy. The systemic usage of substrates is measured via respiratory exchange ratio (RER). A RER of 1.0 represents total usage of carbohydrates while a ratio of 0.7 represents fatty acid usage (values in between represent a mixture). During exercise RER early approaches 1.0 but returns toward 0.7 in extended workouts indicating a shift towards fatty acid oxidation after longer duration [
113].
Different metabolic and mitochondrial alterations related to training have been identified. This has high clinical implication for potential therapeutic targets as mitochondrial dysfunction is one of the key findings in heart failure and as exercise is protective for cardiac mitochondria against ischemia/reperfusion injury in mice [
114]. Rather inconsistent data about changes in the proportion of glucose and fatty acid oxidation in cardiac cells have been gained in the past years from rodent models. Therefore, exact assignment of substrate utilization in response to chronic exercise remains uncertain [
115]. Clear changes have been found in metabolic gene expression and mitochondrial pathways: Expression of genes involved in beta-oxidation of fatty acids and glucose metabolism in the heart differ between exercise-induced physiological cardiac growth and maladaptive pathological cardiac growth. Genes involved in β-oxidation are downregulated in maladaptive cardiac hypertrophy whereas they (including CD36, a fatty acid translocase and scavenger receptor) are found to be upregulated in exercise-induced cardiac hypertrophy [
116]. CD36 deficiency is directly linked to insulin resistance and defective fatty acid metabolism in rats [
117]. In contrast abnormal myocardial fatty acid uptake via redistribution of CD36 from intracellular stores to the plasma membrane was found in early stages of insulin resistance contributing to cardiac lipotoxicity [
118]. The impact of CD36 on cardiac function is not entirely understood. CD36-deficient hearts were found not to be energetically or functionally compromised and were not more vulnerable to ischemia as energy generation through glucose oxidation was able to compensate for the loss of fatty acid-derived energy generation [
119].
The transcriptional co-activators PGC-1α and PGC-1β regulate oxidative phosphorylation and fatty acid oxidation gene expression and control number and size of mitochondria. Heart failure is associated with repressed PGC-1α and PGC-1β gene expression [
120]. In mice with diabetic cardiomyopathy running prevented cellular apoptosis and fibrosis, improved mitochondrial biogenesis, prevented diabetic cardiomyopathy-associated inhibition of PGC-1α, and activated Akt signaling [
121].
Adenosine monophosphate-activated protein kinase is a serine/threonine kinase which participates in regulating cellular energy supply [
122]. Long-term activation of AMPK blocks cardiac hypertrophy as well as NFAT, NF-kB, and MAPK signaling and thus preserves cardiac function in pressure-overload rats [
123]. AMPK deficiency, on the other hand, exacerbates LV hypertrophy in mice [
124]. Swimming-trained rats showed activated AMPK levels with reduced cardiac fibrosis due to inhibition of NADPH oxidase [
125]. This finding has been confirmed as decreased AMPK activity by beta-adrenergic activation exacerbated cardiac fibrosis [
126]. This is interesting as exercise activates AMPK [
127] and consequently might be able to inhibit pathological hypertrophy and cardiac fibrosis.
The intrinsic mitochondrial apoptotic pathway is one of the most important mechanisms of myocyte degeneration in the progression of heart failure [
128]. Exercise induces a cardiac mitochondrial phenotype that resists apoptotic stimuli increasing antioxidant enzymes [
129]. The Bcl-2 pathway is one of those proapoptotic mitochondrial-mediated pathways and has been demonstrated to be critical in regulating apoptosis in aging patients [
130]. Rat hearts showed 12 weeks after training attenuated age-induced elevation in Bax/Bcl-2 ratio and consequently lower apoptotic rates and remodeling [
131].
Another key metabolic pathway induced by exercise is the peroxisome proliferator-activated receptors (PPAR)-pathway. PPAR are transcription factors mediating the development of cardiac hypertrophy and regulating fatty acid metabolism [
132]. Exercise increases PPAR-alpha levels and decreases consequently inflammatory response including TNF-alpha and NF-kB levels [
133]. This is important as PPAR-alpha stimulation downregulates inflammatory molecules and decreases infarct size [
134]. Aging processes decrease PPAR-alpha levels, a finding that could be attenuated in swim-trained rat hearts which contributed to an improvement in fatty acid metabolic enzyme activity [
135].