Beneficial effects of ET for cardiovascular diseases

An accumulating number of cohort studies, systematic reviews, and meta-analyses have documented that ET has multiple beneficial effects for patients with CVDs, such as improving cardiac structure and function, reducing hospitalization, and all-cause mortality, extending life expectancy (Refs.Reference Chaput14–Reference Wen16). A meta-analysis has suggested that achieving the recommended physical activity levels (150 minutes of moderate-intensity aerobic activity per week) can reduce CVD incidence by 17%, CVD mortality by 23%, and type 2 diabetes mellitus (T2DM) incidence by 26% (Ref.Reference Wahid17). Compared to an unhealthy diet and inactivity (UDI), a prospective cohort study has revealed that the reduction in all-cause and CVD mortality is associated with the following lifestyles: a healthy diet and activity (HDA); a healthy diet but inactivity (HDI); an unhealthy diet but activity (UDA) (Ref. Reference Kazemi18). However, Kivimäki and colleagues (Ref. Reference Kivimäki19) demonstrated that physical inactivity is associated with a 24% high risk of CHD, a 16% enhanced risk of stroke, and a 42% higher risk of T2DM. The frequency of adverse cardiovascular events in acute endurance runners is equivalent to that in a population with a diagnosis of CHD (Ref. Reference Nystoriak and Bhatnagar20). Extreme endurance exercise may induce adverse cardiorenal interactions (Ref. Reference Burtscher21). Currently, ET has been prescribed as a medical therapy for different CVDs. In the following section, we will discuss the potential protective effects of ET in CVDs in detail (Figure 1).

Figure 1.

Protective effects of exercise rehabilitation in CVDs. Exercise-based cardiac rehabilitation plays a significant role in the pathophysiological evolution of cardiovascular health, including reducing myocardial oxidative stress and the inflammatory response, improving microvascular dysfunction and cardiac fibrosis, and promoting cardiac metabolism, physiological hypertrophy and cardiomyocyte proliferation. These benefits may reduce the incidence of cardiovascular complications, the rehospitalization rate, and mortality. VCAM1, vascular cell adhesion molecule-1; LOX-1, lectin-like oxidized LDL-receptor-1.

ET reduces myocardial oxidative stress

Reactive oxygen species (ROS), both as subcellular messengers in signal transduction pathways and as contributors to oxidative stress, play beneficial or deleterious roles in the initiation, development, and outcomes of CVDs. The main sources of ROS at the cardiac level are the mitochondrial electron transport chain, xanthine oxidase, NADPH oxidases (more specifically that of NOX5), and nitric oxide (NO) synthase (Ref. Reference Dubois-Deruy22). Under physiological conditions, producing a low level of ROS is equivalent to detoxification, and it plays a pivotal role in cellular signalling and function. This process, termed redox signalling, is defined as the specific and reversible oxidation/reduction modification of cellular signalling components for the regulation of gene expression, excitation-contraction coupling, cell growth, migration, differentiation, and death (Ref. Reference Dubois-Deruy22). In contrast, in pathological situations, ROS causes oxidative modification of major cellular macromolecules (such as lipids, proteins, or DNA) in subcellular organelles, including mitochondria, the sarcoplasmic reticulum, and the nucleus. However, this response leads to atherosclerosis, endothelial and mitochondrial dysfunction, increased blood pressure, and cardiomyocyte hypertrophy (Ref. Reference Zalba and Moreno23).

Not surprisingly, numerous randomized clinical trials investigating antioxidants have been negative, whereas targeting mitochondria will be a promising strategy to improve mitochondrial functionality by nonpharmacological methods, including exercise. In the past few decades, ET has been developed into an established evidence-based treatment strategy for CVDs (Refs. Reference Thomas8, Reference Bull24). A previous study in a mouse model has demonstrated that ET increases endothelial sirtuin 1 (SIRT1) levels and reduces the downregulation of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), nuclear factor erythroid 2-related factor (NRF2), and heme oxygenase 1 (HO-1). ET protects against cardiac damage by inducing hyperlipidaemia-induced oxidative stress, inflammation, and apoptosis (Ref. Reference Pei25). Additional studies in patients with CHD have demonstrated that regular moderate ET attenuates cardiac oxidative stress by decreasing protein carbonyl, SOD, and GSH-Px, as well as increasing GSH and ferric reducing antioxidant power (FRAP) levels (Refs. Reference Taty Zau26, Reference Tofas27). Additionally, oxidative stress is associated with the expression of ncRNAs (Refs. Reference Minjares28, Reference Iantomasi29). Masoumi-Ardakani and colleagues (Ref. Reference Masoumi-Ardakani30) elucidated that ET improves cardiac function in hypertensive individuals by increasing total serum antioxidant capacity, which is related to reduced microRNA-21 (miR-21) and miR-222 levels. Knockdown of lncRNA SNHG8 in MI mice reduces myocardial infarction (MI) size and alleviates myocardial tissue injury and oxidative stress (Ref. Reference Tang31). Similarly, lncRNA NORAD overexpression attenuates doxorubicin (DOX)-induced cardiac pathological lesions by decreasing cardiomyocyte apoptosis and mitochondrial ROS levels (Ref. Reference Guan32). However, further mechanisms of ROS and ncRNAs in ET-induced CVDs remain to be understood.

ET blunts inflammatory pathways

The inflammatory response is an equivocal topic in cardiovascular protection. It is well known that inflammation is involved in the development and progression of CVDs, such as atherosclerosis, hypertension, CHD, and rheumatic heart disease, and it provokes cardiomyocyte damage. Importantly, ET halts the action of inflammatory mediators and the induction of biological pathways to protect the heart (Refs. Reference Metsios33–Reference Crea35). For instance, ET affects macrophage function, including downregulation of the interleukin-1 (IL-1), tumour necrosis factor-α (TNF-α), and nuclear factor (NF)-κB inflammatory cytokines, as well as reducing oxidized LDL and improving antioxidant capacity to blunt the processes of atherosclerosis (Ref. Reference Metsios33). Evidence from a human study shows that aerobic training is beneficial for blood pressure control and CVD risk reduction by decreasing endothelin-1 and the C-reactive protein (CRP), monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, and lectin-like oxidized LDL-receptor-1 inflammatory markers (Ref. Reference Boeno36). A systemic review and meta-analysis have demonstrated that ET reduces CRP, fibrinogen, and von Willebrand factor (vWF) concentrations in CHD subjects (Ref. Reference Thompson37). Nonetheless, further animal and clinical studies with high methodological qualities and large sample sizes are needed to improve evidence-based medicine in this area and to explore the underlying molecular mechanism of different exercise mode-induced inflammation reduction in more CVDs.

NcRNAs play regulatory roles in inflammation and innate immune responses. The expression of lncRNA INKILN is downregulated in contractile vascular smooth muscle cells (VSMCs) but induced in human atherosclerotic vascular diseases (ASVDs) and aortic aneurysms. Knockdown of lncRNA INKILN by siRNA attenuates the expression of a series of proinflammatory genes by blocking IL-1β-induced nuclear localization and the physical interaction between p65 and megakaryocytic leukaemia 1 (MKL1), which is a major transcriptional activator of vascular inflammation (Ref. Reference Zhang38). MiR-15a-5p and miR-199a-3p overexpression decreases inflammatory pathway protein levels, such as IKKα, IKKβ, and p65, and it reduces oxidized LDL and NF-κB activation in VSMCs and patients with atherosclerosis (Ref. Reference González-López39). Moreover, overexpression of miR-340-5p reduces cardiomyocyte apoptosis and inflammation via the HMGB1/TLR4/ NF-κB pathway in myocardial ischemia–reperfusion injury (MIRI) (Ref. Reference Long40).

ET optimizes cardiac metabolism

Cardiac metabolism represents a crucial and significant bridge between health and CVDs. The predisposing factors of CVDs, such as insulin resistance, DM, and obesity, are associated with imbalances in cardiac mitochondrial dynamics, mitochondrial fusion and fission, mitochondrial metabolic dysfunction, and mitophagy (Refs. Reference Fajardo41, Reference Li42). The heart is an important energy-consuming organ, accounting for approximately 30%–40% of mitochondria by volume of cardiomyocytes. Under physiological baseline conditions, the heart is considered an omnivore organ because it uses broad energy substrates. Cardiac ATP is mainly produced from fatty acid oxidative phosphorylationglucose oxidative phosphorylationlactateand other energy sources, including pyruvate, pyruvate, acetate, and branched-chain amino acids (BCAAs). However, under pathological conditions, such as MI, myocarditis, and HF, cardiometabolic substrates switch from major fatty acid oxidation to carbohydrate oxidation (Ref. Reference Ritterhoff and Tian43), because glycolysis consumes less oxygen than fatty acid oxidation and the oxidative phosphorylation products, namely, water and carbon dioxide, are nontoxic to the heart.

Compared to pathological conditions, cardiac workload and myocardial oxygen consumption markedly increase during ET, leading to an increased rate of ATP generation by increasing the use of fatty acid and lactic acid, as well as by reducing the consumption of glucose. However, myocardial glucose is significantly used during long-term exercise, which is related to the progression of cardiac physiological hypertrophy (Refs. Reference Xiong44, Reference Zhang45). A previous study has demonstrated that swimming exercise-induced adaptation leads to cardiac physiological hypertrophy and increases glycolysis, glucose oxidation, fatty acid oxidation, and ATP production (Ref. Reference Robbins and Gerszten46). In addition, ET improves the imbalance of mitochondrial dynamics and abnormal changes in mitochondrial structure in pathological states. Treadmill exercise has been identified to attenuate DM-induced cardiac dysfunction by enhancing the cardiac action of fibroblast growth factor 21 (FGF21) and inducing the AMPK/FOXO3/SIRT3 signalling axis to prevent toxic lipid-induced mitochondrial dysfunction and oxidative stress (Ref. Reference Jin47). A previous study involving ET in a mouse model has reported that ET activates the SIRT1/PGC-1α/PI3K/Akt signalling pathway to attenuate MI-induced mitochondrial damage and oxidative stress (Ref. Reference Jia48). However, the biological mechanism of ET intervention to improve the energy metabolism of CVDs still lacks a theoretical basis and practical measures.

ET improves microcirculation structure and function

Recent invasive investigations have shown that nearly 60% patients of chest pain do not have obstructive CHD (defined as lesions with ≥50% stenosis), which has been realized as a frequent issue encountered in clinical practice (Ref. Reference Schindler and Dilsizian49). This clinical phenomenon is defined as coronary microvascular dysfunction (CMD), which is mainly due to capillary rarefaction and adverse remodelling of intramural coronary arterioles (Ref. Reference Camici50). It has been shown that ET intervention improves microvascular structure and function (Refs. Reference Tanaka51–Reference Koller53). Extensive studies with experimental animals have demonstrated that ET improves coronary capillary angiogenesis and myocardial arteriolarisation, as well as increases coronary capillary exchange capacity and maximal coronary blood flow capacity, thus promoting coronary collateral circulation growth, increasing ischemic threshold and limiting MI size (Refs. Reference Koller53, Reference Merkus54). Additionally, activating NO, PGs and hyperpolarization factors by ET improves hemorheological parameters to reduce prothrombotic risk (Ref. Reference Koller53). However, compared to preserved coronary flow reserve, patients with CMD have a higher prevalence of inducible myocardial ischemia and reduced global perfusion reserve, as well as coronary perfusion efficiency, during ET (Ref. Reference Rahman55). The underlying mechanism merits further investigation. Substantial evidence suggests that ET controls blood pressure throughout the day, including during rest or stressful events. ET enhances endothelium-dependent vascular relaxation through NO release and decreased ROS, and it improves extracellular matrix levels by reducing collagen deposition and matrix metallopeptidase (MMP)-2/9 expression. ET also decreases plasma levels of proinflammatory cytokines, such as TNF-α, IL-1β, and norepinephrine, and it reduces vascular injury via the NF-κB system (Refs. Reference De Ciuceis52, Reference Saco-Ledo56). In a mouse model of MI, Chen et al. (Ref. Reference Chen57) showed that lncRNA Malat1 repairs the cardiac microcirculation by mediating the miR-26b-5p/Mfn1 pathway to block effects on mitochondrial dynamics and apoptosis.

In clinical practice, invasive coronary angiography, positron emission tomography (PET), computed tomography (CT), cardiac magnetic resonance (CMR), and left ventricular contrast echocardiography are suitable for the noninvasive detection of CMD (Refs. Reference Schindler and Dilsizian49, Reference Ekenbäck58, Reference Schindler59), but these methods still need to be further tested in large-scale randomized clinical trials for intensive and individualized treatment. Therefore, more investigations should be undertaken to reveal different adaptive changes induced by different types, models, and durations of ET in different CVD populations.

ET promotes cardiac repair and regeneration

The end-stage manifestation of many CVDs is HF, of which the pathological driver is death and loss of cardiomyocytes and supporting tissues. Although adult mammalian hearts have limited regenerative capacity, the rate of regeneration is extremely low and declines with age. There are no effective treatment strategies to supplement injured cardiomyocytes and promote cardiac regeneration. Recent advances have verified that regular ET promotes cardiac repair and regeneration by inducing physiological cardiac hypertrophy, inhibiting myocardial apoptosis and necrosis, improving cardiac metabolism, and promoting cardiomyocyte proliferation (Refs. Reference Bo60, Reference Jiang61). Vujic et al. (Ref. Reference Vujic62) found that 8 weeks of voluntary running exercise significantly increased the number of new cardiomyocytes in normal adult and MI mouse hearts. Another study has also demonstrated that running exercise restores cardiomyogenesis in aged mice, which may be associated with circadian rhythm pathways (Ref. Reference Lerchenmüller63). ET, as a physiological stimulus, plays an important cardioprotective role in adult zebrafish by inducing cardiomyocyte proliferation (Ref. Reference Rovira64). Recently, animal studies have revealed that ncRNAs are linked to the control of cardiomyocyte regeneration, renewal, and proliferation. For instance, swimming or wheel exercise upregulates miR-222 expression, which targets the Kip1 (P27), homeodomain-interacting protein kinase 1/2 (HIPK1/2), and homeobox-containing 1 (HMBOX1) to induce the proliferation and growth of cardiomyocytes (Ref. Reference Liu65). Other miRNAs, such as miR-342-5p (Ref. Reference Hou66), miR-486 (Ref. Reference Bei67), and miR-133 (Ref. Reference Palabiyik68), also play significant roles in regulating cardiac growth and survival in response to ET. Furthermore, swimming training promotes cardiomyocyte growth and attenuates cardiac remodelling in an MIRI mouse model by upregulating lncRNA CPhar expression, which inhibits the expression of transcription factor 7 (ATF7) by sequestering CCAAT/enhancer binding protein β (C/EBPβ) (Ref. Reference Gao69). Although changes in ncRNA expression in animal studies are at least in part transferable to treatment regimes, more work is still needed to validate their safety and applicability for clinical application.

ET alleviates cardiac fibrosis

Cardiac fibrosis (CF), mainly characterized by the unbalanced production and degradation of extracellular matrix (ECM) proteins, is the main pathological process of CVDs, and it leads to cardiac dysfunction, arrhythmogenesis, and adverse outcomes (Ref. Reference Pesce70). Attenuating CF is a key strategy for maintaining cardiac function and improving the prognosis of patients with CVDs. In addition to traditional drug therapy and new interventions, such as chimeric antigen receptor (CAR)-T-cell therapy (Refs. Reference Friedman71, Reference Frantz72), increasing evidence from clinical and animal studies suggests that ET-based CR should be taken into consideration to prevent the progression of adverse CF (Refs. Reference Farsangi73–Reference Yin76). For example, ET reduces the fibrosis-related protein levels of AT₁R, fibroblast growth factor 23 (FGF23), lysyl oxidase like-2 (LOX-2), transforming growth factor (TGF)-β, p-Smad2/3, TIMP-1/2, MMP-2/9, and collagen I (Refs. Reference Hong77, Reference Yang78). Mechanistically, ET suppresses LOX-2/TGF-β-mediated fibrotic pathways to prevent CF and myocardial abnormalities in early-aged hypertension (Ref. Reference Hong77). In addition, ET increases FGF21 protein expression and regulates the TGF-β1-smad2/3-MMP2/9 axis (Ref. Reference Ma79). ET markedly inhibits lncRNA MIAT expression and upregulates miR-150 to improve cardiac remodeling by inhibiting P2X7 purinergic receptors (P2X7Rs) in diabetic cardiomyopathy (DCM) (Ref. Reference Wang80). Additionally, ET plays a functional role in HF and DOX-induced cardiotoxicity (Refs. Reference Yang78, Reference Feng81, Reference Hsu82). Although basic and clinical trials associated with antifibrotic drugs have been performed, future studies should focus on exploring the underlying pathophysiological mechanisms in the onset and progression of CF to determine integrated and personalized therapeutic strategies. In summary, the early identification, diagnosis, and management of CF are vital in improving the survival and prognosis of CVD patients.

Exercise mediates cardiac protection by ncRNAs

Most recently, an increasing number of studies have indicated that epigenetic modifications are involved in the promotion of cardiac health and the prevention of CVDs. Lifestyle factors, such as exercise and diet, extensively induce epigenetic modifications, including DNA/RNA methylation, histone posttranslational modifications, and ncRNAs (Refs. Reference Wu83, Reference Abraham84). For example, a low-protein diet causes altered sncRNA content in spermatozoa, which is associated with altered levels of lipid metabolites in offspring and decreased expression of specific genes starting in two-cell embryos (Ref. Reference Klastrup85). However, no reported studies have evaluated the link of exercise-induced DNA methylation in cardiac tissue, indicating that the action of different epigenetic mechanisms in EIC needs further study.

Evidence suggests that ncRNAs may be used as novel biomarkers, offering innovative prospects for the diagnosis, treatment, and prognosis of CVDs. In addition to the changes resulting from pathological conditions, ncRNAs and related signalling pathways also undergo changes due to ET (Figure 2). For example, miR-1-3p is an emerging biomarker of high-volume maximal endurance exercise, while in low-volume doses there is an absence of response in low-volume doses (Ref. Reference Fernández-Sanjurjo98). CircRNA MBOAT2 expression is significantly decreased after 24 h of marathon running and can be used as a biomarker for detecting cardiopulmonary adaptation (Ref. Reference Meinecke96). There are many studies of miRNA involvement in exercise adaptations, and far less is currently known about lncRNAs and circRNAs (Table 1). NcRNAs and their signal pathways respond differently to exercise intensity, frequency, and tolerance. Additionally, the correlation between exercise prescription and ncRNAs needs to be further researched in both animal models and clinical cohort studies.

Figure 2.

Exercise-induced ncRNAs and their regulated pathways in CVDs. The regulation of ncRNAs contributes to the progression of various CVDs, including hypertension, DCM, ASVDs, MIRI, MI, HF, and DOX-induced cardiomyopathy.

Table 1.

Exercise mediates ncRNAs in cardiovascular diseases

Notes: ↑ represents ‘enhanced effect’; ↓ represents ‘reduced effect’; NA represents ‘not available’; *represents ‘cell transfection’; ^#represents ‘genetic animal model’.

Exercise-induced ncRNAs in MI

MI is a leading cause of cardiovascular death and chronic HF worldwide (Ref. Reference Tsao1). Cardiomyocytes undergo a series of pathological adaptations after MI, including myocardial ischemia, hypoxia, inflammatory response, necrosis, progressive CF, and ventricular enlargement. Persisting structural cardiac abnormalities are associated with arrhythmias, HF, and sudden cardiac death. Although percutaneous coronary intervention and drugs have become the predominant treatment for MI, these strategies cannot reverse or attenuate the biological process, eliminate risk factors, and consistently improve patient outcomes.

It has been demonstrated that regular ET significantly improves cardiac structure and function by rescuing post-MI stunned myocardium (Refs. Reference Pelliccia4, Reference Dibben9). Furthermore, exercise-mediated ncRNAs have great significance in the biological regulation of MI. in vivo studies have shown that 4 weeks of ET increases miR-126 expression and reduces the expression of PIK3R2 and SPRED1. in vitro results have demonstrated that miR-126 promotes angiogenesis by the PI3K/Akt/eNOS and MAPK signalling pathways, subsequently improving of MI cardiac function, including increasing left ventricular systolic pressure (LVSP) and + dp/dt_max and decreasing left ventricular end-diastolic pressure (LVEDP) and collagen volume fraction (Ref. Reference Song87). Compared to the control group, ET reduces cardiomyocyte apoptosis and improves CF and systolic function by decreasing lncRNA MIAT expression and increasing the expression of lncRNA H19 and lncRNA GA55 (Ref. Reference Farsangi73). Further exploration has shown that overexpression of lncRNA H19 also dramatically alleviates myocardial infarct size and inflammation by sponging miR-22-3p to target lysine (K)-specific demethylase 3A (KDM3A) (Ref. Reference Zhang99). Likewise, other studies have illustrated that lncRNA H19 plays an essential role in regulating the pathological processes of CVDs by acting as a molecular sponge or interacting with various proteins to target gene expression (Ref. Reference Su100). The above results indicate that lncRNA H19 is a potential marker or a promising target for CVD treatment.

Clinical outcomes and prognosis vary with individual differences in pathophysiological mechanisms. In response to the common cardiac remodelling in the early and late stages of MI, there are currently novel therapeutic strategies, including SGLT2-i, inflammatory modulators, and silencing small RNAs, have been developed (Ref. Reference Frantz72). Furthermore, circulating markers can be combined with novel cardiac imaging techniques, such as CMR and myocardial work index of the left ventricular 17 segment by echocardiography, to help reveal the pathophysiological mechanism of cardiomyopathy and better guide personalized treatment.

Exercise-induced ncRNAs in myocardial ischemia-reperfusion injury

Recovering reperfusion after MI can cause irreversible detrimental effects known as MIRI, including myocardial stunning, reperfusion arrhythmia, no-reflow phenomenon, and lethal reperfusion injury. Pathological changes, such as inflammation, apoptosis, autophagy, and neurohumoral activation, are considered to have the same underlying cause as MIRI (Ref. Reference Marinescu101). Recent findings have revealed that novel ncRNAs are involved in a variety of important biological processes and the development of MIRI (Ref. Reference Li102). Systemic reviews and meta-analyses have also shown that ET increases the left ventricular ejection fraction, cardiac output, and coronary blood flow (Ref. Reference Song103). Increased miR-17-3p inhibits TIMP 3 expression to enhance cardiomyocyte proliferation by activating EGFR/JNK/SP-1 signalling (Ref. Reference Shi86). In addition, miR-17-3p indirectly regulates the PTEN/Akt signalling pathway to promote cardiomyocyte hypertrophy in vivo and in vitro (Ref. Reference Shi86). Bei et al. reported that downregulation of miR-486 occurs in both MIRI in vivo and OGDR-treated cardiomyocytes in vitro. However, AAV9-mediated miR-486 overexpression in a mouse model of MIRI significantly reduces infarct size, the Bax/Bcl-2 ratio, and caspase-3 cleavage (Ref. Reference Bei67). Functionally, increasing miR-486 is protective against MIRI and myocardial apoptosis through activating the Akt/mTOR pathway to inhibit PTEN and FoxO1 expression (Ref. Reference Bei67). Concurrently, Hou et al. revealed a novel endogenous cardioprotective mechanism in which long-term exercise-derived circulating exosomal miR-342-5p protects the heart against MIRI. Mechanistically, miR-342-5p targets caspase 9 and JNK 2 to inhibit hypoxia/reoxygenation-induced cardiomyocyte apoptosis; it also enhances survival signalling (p-Akt) by targeting phosphatase gene Ppm1f (Ref. Reference Hou66). Other miRNAs, such as miR-125-5p, miR-128-3p, and miR-30d-5p, are also important regulators of EIC against MIRI (Ref. Reference Zhao89). However, there are still few reports about exercise-mediated other ncRNAs (lncRNAs and circRNAs) in MIRI. Therefore, further studies are needed to clarify the underlying mechanisms of exercise-mediated ncRNAs in the occurrence and development of MIRI.

Exercise-induced ncRNAs in HF

Exercise-based CR has been recommended as a clinical consultation for HF by international guidelines. Individualized exercise prescription is effective in improving the 6-minute walk distance, cardiopulmonary function, incidence of complications, and quality of life (Refs. Reference McDonagh104, Reference Heidenreich105). Emerging ncRNAs have been found to play roles in EIC and HF (Ref. Reference Ma and Liao106). For instance, Stølen et al. (Ref. Reference Stølen90) found that moderate- and high-intensity ET decrease the expression of miR-31a-5p, miR-214-3p, and miR-495-5P in post-MI HF mice, which reduces arrhythmia susceptibility by slowing Ca²⁺ transient decay and decreasing collagen content, such as CTGF, collagen 1α1, and TGFβ1 expression. Other ncRNAs, such as miR-1, miR-133, miR-15 family, and circRNA-010567, inhibit myocardial fibrosis by regulating related pathways, including Ang-II, MAPKs, and TGF-β (Refs. Reference Ma and Liao106, Reference Wang107). However, the number of exercise-induced lncRNAs and circRNAs is limited, and their roles in EIC for HF are unclear. As reported by Hu et al. (Ref. Reference Hu92), aerobic exercise improves left ventricular remodelling and cardiac function by inhibiting lncRNA MALAT1 to regulate the miR-150-5p/PI3K/Akt signalling pathway. Overexpression of lncRNA ExACT1 has been shown to aggravate pathological hypertrophy and HF, while inhibition of lncRNA ExACT1 protects against CF and dysfunction by inducing physiological hypertrophy and cardiomyogenesis (Ref. Reference Li93). The potential regulatory mechanism is that the function of lncRNA ExACT1 is regulated by miR-222, calcineurin signalling, and Hippo/Yap1 signalling through dachsous cadherin-related 2 (DCHS2) (Ref. Reference Li93), which provides a potentially tractable therapeutic target for EIC in HF.

Exercise-induced ncRNAs in cardiac hypertrophy

Cardiac hypertrophy is characterized by a marked increase in myocardial mass index, and it can be categorized as physiological or pathological hypertrophy. Physiological myocardial hypertrophy (PMH) is an adaptive and reversible cardiac growth under chronic exercise stimulation and exerts cardioprotective effects. Conversely, pathological hypertrophy develops in response to chronic pressure or volume overload in disease settings, such as transverse aortic constriction (TAC) and aortic stenosis, resulting in adverse cardiac remodelling and dysfunction. Evidence suggests that ncRNAs are directly involved in and regulate different pathological stresses of cardiac hypertrophy. For instance, knocking down or overexpression of miR-30d and certain lncRNAs (Chast, Chaer, NRON, Mhrt, and H19) plays important regulatory roles in a mouse model of TAC-induced cardiac hypertrophy (Refs. Reference Lerchenmüller108, Reference Makarewich and Thum109).

The roles of ncRNAs in exercise-induced cardiac hypertrophy are supported by findings in different animal models and training programs. The expression of miR-21, miR-27a, and miR-143 is different after aerobic swimming training in mice presenting physiological left ventricular hypertrophy compared with sedentary controls (Ref. Reference de Gonzalo-Calvo97). Moreover, silencing lncRNA Mhrt779 attenuates the antihypertrophic effect of exercise hypertrophic preconditioning (EHP) in TAC mice and in cultured cardiomyocytes treated with Ang-II, while overexpression of lncRNA Mhrt779 enhances the antihypertrophic effect. Mechanistically, ET increases resistance to pathological pressure overload by an antihypertrophic effect mediated by the lncRNA Mhrt779/Brg1/Hdac2/p-Akt/p-GSK3β signalling pathway (Ref. Reference Lin94). Similarly, lncRNA CPhar and lncRNA ExACT1 have emerged as important mediators underpinning the process of exercise-induced PMH (Refs. Reference Gao69, Reference Li93). Although some circRNAs, such as circRNA sh3rfe (Ref. Reference Ma110), circRNA Cacna1c (Ref. Reference Lu111), circRNA 0001052 (Ref. Reference Yang112), and circRNA Ddx60 (Ref. Reference Zhu95), have been found to be closely related to cardiac hypertrophy, only circRNA Ddx60 has been identified to be needed for exercise-induced PMH in mice on the basis of a forced swim training model. CircRNA Ddx60 contributes to the antihypertrophic effect of EHP by binding and activating eukaryotic elongation factor 2 (eEF2) (Ref. Reference Zhu95).

Notably, multiple factors, such as genetic background, species, and gender differences, may influence the adaptations and outcomes of exercise. Konhilas et al. (Ref. Reference Konhilas113) found that female mice have a greater increase in PMH after treadmill or voluntary wheel running. It has been revealed that common genetic variants are important pathogenic factors in hypertrophic cardiomyopathy, suggesting the existence of non-Mendelian inheritance patterns with ethnic differences (Ref. Reference Wu114). Current knowledge on the different expression, regulation, and pathology-related functions of ncRNAs in terms of both sex and age is limited (Refs. Reference Jusic115, Reference Rounge116). Additionally, whether genetic or sex differences influence the expression of ET-induced ncRNAs and their signalling pathway responses remain to be clarified.

Exercise-induced ncRNAs in other CVDs

T2DM is a metabolic disorder characterized by hyperglycaemia, hyperinsulinemia and high insulin resistance, which causes macrovascular and microvascular complications, such as atherosclerosis, CHD, and diabetic cardiomyopathy (DCM). Increasing ncRNAs have been recommended as exercise indicators for cardiovascular prescriptions and as preventive or therapeutic targets for cardiovascular complications in T2DM. MiR-126 induced by ET has been found to decrease vascular inflammation and apoptosis via the PI3K/Akt pathway, promote angiogenesis via the VEGF pathway, and increase cardiac autophagy via the PI3K/Akt/mTOR pathway (Refs. Reference Lew88, Reference Ma117). Long-term ET protects against vascular endothelial injury of insulin resistance by downregulating the expression of several lncRNAs, including FR030200 and FR402720 (Ref. Reference Liu118) and then attenuating the progression of atherosclerotic CVD. Similarly, lncRNA NEAT1 induces endothelial pyroptosis by binding Kruppel-like factor 4 (KLF4) to promote the transcriptional activation of the key pyroptotic protein, NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), whereas exercise reverses these effects (Ref. Reference Yang91).

In addition, ncRNAs play significant roles in other CVDs, such as valvular heart diseases (Ref. Reference Chen119), cardiomyopathy (Ref. Reference Liu and Chong120), myocarditis (Ref. Reference Zhang121), and pulmonary hypertension (Ref. Reference Ali122). The main pathophysiological processes also include inflammation, oxidative stress, apoptosis, extracellular matrix reorganization, and fibrosis, but they are still not sufficiently understood in terms of biological mechanisms. Although an increasing number of studies and guidelines have demonstrated that exercise-based CR has beneficial effects on these CVDs (Refs. Reference Hu10, Reference Humbert123, Reference Koh124), the specific molecular mechanisms and signaling pathways of exercise-induced ncRNAs await further investigation. Consequently, this limits improvements in novel therapeutic strategies and biomarkers of risk assessment, as well as prevention and diagnosis of CVDs. In addition, due to significant differences in cardiopulmonary function and different recovery processes after CVD events, it is necessary to develop an optimal individualized exercise-based CR program oriented to clinical problems according to the condition of patients.