Imaging assessment of PCH can be performed using advanced modalities such as three-dimensional echocardiography (3DE), tissue Doppler imaging (TDI), and cardiac magnetic resonance imaging (CMR), which allow for accurate evaluation of cardiac structure, function, and remodeling. 3DE offers a robust approach reconstructing cardiac anatomy by capturing volumetric data in real time. One of its key advantages is the ability to accurately measure left ventricular ejection fraction (LVEF), a critical parameter in the assessment of PCH (33). In healthy individuals, LVEF typically falls within the range of 55%–70%. During PCH, the left ventricular end-diastolic volume (LVEDV) increases significantly, often accompanied by a compensatory rise in stroke volume (SV). Despite the volumetric expansion, LVEF remains within the normal range or may even exhibit a mild increase, indicating preserved or augmented systolic performance (13, 34, 35). This coordinated volume expansion is associated with the sustained activation of the Insulin-like Growth Factor 1 (IGF-1)/Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (Akt) signaling pathway, which in turn leads to uniform myocardial thickening rather than localized hypertrophy (36). In addition to LVEF, the left ventricular mass (LVM) and the left ventricular mass index (LVMI) also serve as crucial indicators for evaluating PCH. Reference values suggest normal LVM ranges from 73 to 115 g in males and 62–95 g in females, with normal LVMI thresholds of ≤115 g/m² and ≤95 g/m², respectively. In individuals with PCH, both LVM and LVMI show mild increases that remain below the diagnostic thresholds for PMH, though considerable inter-individual variability may be observed. The molecular basis involves increased protein synthesis regulated by the mammalian target of rapamycin complex 1 (mTORC1) and limited myocardial cell proliferation mediated by the Hippo-YAP signaling pathway (35, 37, 38). Despite the advantages of 3DE in providing detailed insights into cardiac structure and function, the technique is subject to several limitations. These include susceptibility to patient-specific factors, greater computational and storage requirements, and relatively lower temporal and spatial resolution compared to other imaging methods.

TDI is an echocardiographic technique that quantifies myocardial motion by detecting Doppler frequency shifts generated by tissue movement, thereby enabling the construction of energy, velocity, and acceleration maps. This method allows for accurate assessment of both systolic and diastolic cardiac function (39). Key functional parameters derived from TDI include the systolic s' wave and the diastolic E/e' ratio. The s' wave reflects the peak velocity of myocardial contraction during systole and exhibits a strong correlation with the LVEF. In healthy individuals, the lateral mitral annular s' wave typically ranges between 7 and 10 cm/s, although this lower boundary may be as low as 5.4 cm/s depending on factors such as age, sex, and equipment calibration (40–42). In case of exercise-induced PCH, the s' wave generally remains within normal levels or shows a modest increase (43). The E/e’ ratio serves as a surrogate marker for estimating the left ventricular filling pressure (LVFP). An E/e’ ratio below 8 is indicative of normal LVFP, whereas values between 8 and 15 fall into an intermediate zone that necessitates supplementary clinical parameters—such as left atrial volume (LAV)—for accurate interpretation. In the setting of PCH, this ratio may exhibit a slight elevation, reflecting adaptive modifications in diastolic function (44–46). This phenomenon reflects adaptive remodeling through the Calcineurin (CaN)/Nuclear Factor of Activated T-cells (NFAT) signaling pathway, which facilitates the rapid Ca²⁺ reuptake process. When the E/e’ ratio is in the “gray zone” accompanied by a decrease in the s' wave, it indicates dysfunction of the PI3K/Akt-m⁶A methylation axis, suggesting potential pathological risks (17). TDI offers several advantages, including high temporal resolution, real-time quantitative assessment, and broad clinical applicability. Nonetheless, its limitations—such as angle dependency and the need for high frame rates—must be taken into account when interpreting results.

CMR is based on the principle of nuclear magnetic resonance, whereby hydrogen protons within myocardial tissue resonate under a strong magnetic field and radiofrequency pulses. The resulting signals are reconstructed into high-resolution, multi-plane, and multi-parameter images, enabling detailed assessment of cardiac morphology and function. Owing to its superior spatial resolution and tissue characterization, CMR is regarded as the gold standard for evaluating myocardial structure and function, and it plays a pivotal role in the clinical assessment of PCH (47). CMR allows precise quantification of parameters such as myocardial thickness, ventricular volumes, and ejection fraction, thereby providing robust diagnostic support. For example, measurements of left ventricular wall thickness (LVWT) are commonly used to evaluate the extent of myocardial hypertrophy (MH). In healthy adults, LVWT is typically 9–10 mm and interventricular septal thickness (LVST) 10–12 mm. In PCH, LVWT and LVST may increase to approximately 13–16 mm, usually accompanied by enhanced diastolic function (E/e’ ≤8), preserved myocardial tissue integrity (absence of fibrosis), and left ventricular dilation (≥10% increase in end-diastolic volume) (48, 49). Comparative studies using CMR have demonstrated that elite endurance athletes exhibit greater LVWT, ventricular diameters, and volumes than non-athletes (50). Gender differences have also been observed, with male athletes generally showing larger cardiac mass and volume than females, while age and ethnicity further influence the degree of PCH (51). Importantly, CMR can detect subtle myocardial alterations, including fibrosis and edema, which are essential for distinguishing PCH from PMH. Despite these advantages, limitations such as high cost, long examination times, and the requirement for patient cooperation restrict its application in large-scale population screening (52).

Laboratory assessment of PCH can be performed using myocardial biomarkers, which provide insights into cardiomyocyte function and remodeling. Commonly evaluated biomarkers include cardiac troponin (cTn), B-type natriuretic peptide (BNP), galectin-3 (Gal-3), and markers of ECM turnover. These indicators are valuable for detecting subtle changes in myocardial stress, injury, and remodeling, thereby complementing imaging techniques in the evaluation of PCH.

cTn comprises three subunits: troponin T (cTnT), troponin I (cTnI), and troponin C (cTnC). Of these, cTnT and cTnI exhibit high specificity and sensitivity for detecting myocardial injury or functional alterations. Under resting physiological conditions, circulating levels of cTnT and cTnI are minimal. However, during physical exertion, increased oxidative stress and changes in myocardial membrane permeability may facilitate the transient release of these proteins into the bloodstream. This phenomenon is attributed to reversible cellular stress rather than irreversible cardiomyocyte damage (53–55). Reported reference values for cTnT and cTnI in healthy individuals typically range from 0.001 to 0.05 ng/ml, although variations can occur depending on the analytical method, age, and sex (56).

For instance, a study examining cTnT concentrations in cyclists following varying exercise intensities demonstrated that moderate and high-intensity exertion led to a significant elevation in cTnT levels, whereas low-intensity activity produced no notable change. Importantly, cTnT levels returned to baseline after a recovery period, suggesting that such elevations reflect physiological responses to exercise rather than pathological myocardial injury (53). During moderate-to-high-intensity exercise, sustained mechanical stress on the cellular phospholipid bilayer results in localized membrane injury. The synthesis of membrane repair protein driven by IGF-1/PI3K/Akt pathway cannot fully keep pace with the rate of damage, leading to transient release of cTn. Concurrently, heightened energy demand excessively activates fatty acid oxidation (FAO) pathways, promoting the influx of free fatty acids (FFAs) into mitochondria and triggering excessive production of reactive oxygen species (ROS). ROS oxidize phospholipids such as phosphatidylcholine, destabilizing membrane integrity and facilitating the efflux of cTnT and cTnI through disrupted membrane gaps, ultimately leading to marked elevation of their serum concentrations (57, 58). It is noteworthy that cTn levels typically peak within 1–4 h following exercise and gradually return to baseline within 24–72 h. The magnitude of elevation and recovery kinetics, however, vary according to exercise modality. Endurance training is often associated with a pronounced rise in cTn and a prolonged normalization period, whereas resistance training generally induces a more modest elevation with a faster return to baseline (59, 60).

BNP is an endogenous hormone predominantly secreted by ventricular cardiomyocytes in response to increased wall tension. It exerts natriuretic, diuretic, and vasodilatory effects, with its dynamic changes regulated by the concurrent modulation of the CaN/NFAT pathway and FAO metabolic pathways activated by exercise. These changes reflect the cardiac adaptation to exercise (29, 61). In healthy individuals at rest, BNP levels are generally below 100 pg/ml. During exercise-induced PCH, increased ventricular wall tension leads to elevated intracellular Ca²⁺ concentrations, which bind to calmodulin (CaM) and activate CaN. CaN catalyzes the dephosphorylation of NFAT, which translocated to the nucleus and forms a complex with GATA binding protein 4 (GATA4), significantly enhancing BNP gene expression. Additionally, adrenergic signaling, mitogen-activated protein kinase (MAPK) pathways, and FAO-related signaling also contribute to this regulatory process. Under these signals, BNP secretion increases. This transient elevation, typically remaining below 200 pg/ml, is considered a normal physiological response and is not associated with adverse clinical outcomes in most cases. However, sustained BNP levels ≥300 pg/ml, especially when accompanied by clinical symptoms, may warrant further evaluation for potential cardiac dysfunction (62, 63). For example, Hosseini et al. reported elevated BNP concentrations in soccer players following competitive matches, although the levels remained well below thresholds indicative of heart failure (64). Interestingly, longitudinal observations have shown that serum BNP concentrations tend to decrease with increased cumulative training duration, suggesting an adaptive remodeling process in cardiac function in response to prolonged athletic activity (65). Furthermore, BNP typically normalizes more rapidly than cTn after exercise. Evidence indicates that BNP levels peak within 1–4 h post-exercise and return to baseline within 24 h. Notably, endurance exercise induces a greater elevation in BNP compared with resistance training, largely due to its volume overload stimulus. Despite differences in recovery kinetics between exercise modalities, these responses remain within the spectrum of physiological regulation (66, 67).

Gal-3 is both a fibrotic mediator and an inflammatory regulator, playing a pivotal role in diverse physiological and pathological processes (68). In healthy adults, normal serum Gal-3 levels typically range from 11.8 to 16.3 ng/ml, though values vary with detection method, age, and sex (69, 70). In older adults, downregulation of miR-222 reduces its inhibitory effect on Homeobox Containing 1 (Hmbox1), leading to the activation of the Transforming Growth Factor-β (TGF-β)/Smad pathway and the accumulation of inflammation and fibrosis, resulting in slight elevation of serum Gal-3 (71, 72). Research has shown that during exercise-induced PCH, the IGF-1/PI3K/Akt pathway activation results in phosphorylation of specific serine/threonine residues on Fork head Box O (FOXO), which helps suppress pro-inflammatory cytokine release, thereby reducing macrophage recruitment and activation and subsequently lowering Gal-3 production. Moreover, upregulation of miR-222 during exercise inhibits Hmbox1 mRNA expression, further suppressing TGF-β/Smad pathway activation and reducing Gal-3 production in fibroblasts. In PCH, serum Gal-3 levels remain normal or slightly reduced. In contrast, PMH, with insufficient IGF-1/PI3K/Akt pathway activation, leads to substantial secretion of Gal-3 from macrophages and fibroblasts, resulting in significantly elevated serum levels (73–76).

ECM turnover markers are biological indicators reflecting the dynamic balance between ECM synthesis and degradation. These markers are critical for assessing tissue fibrosis, inflammatory status, and related pathological conditions (77). In the context of PCH, ECM turnover markers aid in distinguishing physiological cardiac adaptation from pathological fibrosis. Commonly measured biomarkers include Procollagen Type I N-Terminal Propertied (PINP), Procollagen Type III N-Terminal Propertied (PIIINP), and Matrix Metalloproteinase-9 (MMP-9) (78). For reference, serum PINP and PIIINP levels in healthy adults are approximately 22–75 ng/ml (electrochemiluminescence immunoassay) and 2.5–5.5 ng/ml (radioimmunoassay), respectively, though values may vary with age, exercise, and assay methodology (79, 80). In PCH, PINP and PIIINP levels typically remain within the normal range or exhibit only mild, transient increases following exercise (81). Slight increases in PINP and PIIINP levels are likely due to the activation of signaling pathways such as Hippo-YAP, IGF-1/PI3K/Akt, and RNA m⁶A methylation, promoting protein synthesis and cellular growth. These pathways may also prevent pathological fibrosis by blocking TGF-β/Smad signaling and downregulating ANP/BNP expression. As a result, fibroblasts maintain a moderate activation state, synthesizing type I and III collagen, which ultimately leads to a mild elevation in serum PINP and PIIINP levels (81–83).

These elevations generally peak within hours post-exercise and return to baseline within 24–72 h, indicating that ECM remodeling during PCH is reversible and represents a normal physiological adaptation. By contrast, in PMH, PINP and PIIINP levels remain persistently elevated, reflecting sustained fibrosis and impaired diastolic function (84, 85). Notably, the response of ECM turnover markers to exercise differs from that of cTn and BNP, as ECM markers show a more moderate increase with a longer recovery period, suggesting that ECM remodeling is a sustained, rather than acute, process. These dynamic changes provide a valuable molecular-level tool for differentiating PCH from PMH.

The electrocardiogram (ECG) is a non-invasive diagnostic method that captures the heart's electrical activity via surface electrodes, translating the depolarization and repolarization of myocardial cells into characteristic waveform patterns. It serves as a crucial tool for assessing physiological and pathological changes in PCH (86, 87).

During exercise-induced PCH, several characteristic ECG alterations can be observed, among which increased QRS complex amplitude is particularly common (88). In the precordial leads, voltage augmentation may be evident in RV5 or RV6, exceeding the normal upper limit of 2.5 mV. In the limb leads, the R wave amplitude in lead aVL can surpass 12 mm, the R or S wave in lead I may exceed 15 mm, and the R wave in lead aVF may also be greater than 15 mm. A distinctive pattern is when the voltage in RV6 exceeds that in RV5 (S-type), which is attributed to an enhanced myocardial depolarization vector associated with PCH (89–91). Studies analyzing ECG data from endurance athletes with prolonged training have shown that increased QRS amplitude is common and significantly correlates with both the duration and intensity of training (92). ST-T segment abnormalities constitute another frequent ECG feature of PCH. In leads predominantly displaying R waves, T waves may appear deeply inverted, biphasic, or upright, while the ST segment can demonstrate horizontal or upward sloping elevation (typically >0.1 mV) or downward sloping depression. Marked elevation of V3 and V4, accompanied by upward sloping ST segments and upright T waves, reflects altered myocardial repolarization induced by PCH (93, 94). Observations in elite athletes following high-intensity training indicate that ST segment elevation with increased T wave amplitude in leads V3–V5 is common, and these training-induced changes typically normalize after a period of rest (95).

It is important to recognize the limitations of ECG in the assessment of PCH. Firstly, the ECG alterations described above are not specific to PCH; similar increases in QRS complex amplitude can also occur in conditions such as hypertensive heart disease and hypertrophic cardiomyopathy, necessitating careful differential diagnosis (96, 97). Secondly, in mild cases of PCH, the ECG may appear normal, potentially resulting in missed diagnoses. Moreover, although ECG reflects myocardial electrical conduction, it does not directly quantify left ventricular wall thickness, and its accuracy can be affected by factors such as heart rate, body size, and comorbid cardiac conditions (98). Consequently, the evaluation of PCH should be comprehensive, integrating medical history, clinical symptoms, physical findings, and complementary diagnostic tests (Table 2).

Endurance exercise is characterized by sustained, moderate-intensity physical activity performed over an extended duration, requiring the integrated function of the cardiovascular and skeletal muscle systems (100). During prolonged endurance activities such as running, cycling, or swimming, the primary hemodynamic adaptations include increased heart rate and SV, resulting in a marked elevation of cardiac output. Simultaneously, enhanced skeletal muscle contraction and respiratory effort augment venous return to the heart. In response to this chronic volume overload, the heart undergoes structural remodeling, manifested primarily as chamber dilation and the progressive development of eccentric hypertrophy (101, 102). Parry-Williams et al. reported that athletes engaged in long-term endurance training exhibit cardiac changes including thickening of the left ventricular wall and chamber enlargement, with these adaptations being more prominent in older athletes (103). Similarly, research by the American Physiological Society demonstrated that one year of continuous endurance training resulted in increased the LVEDV and the LVM, along with enhanced myocardial contractility, while ventricular wall thickness remained largely unchanged. These findings suggest that endurance training promotes eccentric hypertrophic remodeling rather than concentric thickening of the myocardium (104). Experimental studies in animal models support these findings; for instance, rats subjected to daily swimming (60 min per session, five times per week) for 10 weeks developed eccentric cardiac hypertrophy, with the degree of remodeling positively correlated with exercise frequency (105). Mechanistically, the sustained elevation in venous return imposes chronic diastolic wall tension, triggering elongation of sarcomeres—the fundamental contractile units of cardiomyocytes—along the longitudinal axis. This leads to an increase in cardiomyocyte length without a corresponding increase in cell diameter, characteristic of eccentric hypertrophy (106–108).

Although long-term endurance exercise confers numerous cardiovascular benefits, the relationship between exercise intensity, duration, and the threshold for maladaptive cardiac remodeling remains controversial. Increasing evidence indicates that prolonged excessive endurance training may exert detrimental effects on cardiac structure and function. In a study of 40 athletes participating in high-intensity endurance events, such as marathons and triathlons, post-race assessments revealed a marked reduction in right ventricular ejection fraction (RVEF) alongside elevated circulating cardiac troponin (cTn) levels, with a linear correlation between the two. Further myocardial evaluation showed that 12% of these athletes exhibited myocardial fibrosis, and this subgroup had accumulated more years of endurance training compared to their counterparts (109). These findings underscore that excessive endurance exercise can negatively impact cardiac health, particularly affecting the right ventricle. A study in rats reported that 16 weeks of high-intensity training induced eccentric hypertrophy, accompanied by left ventricular diastolic dysfunction and significant myocardial fibrosis in the atria and right ventricle. However, these changes were reversible after the cessation of exercise, suggesting that an excessive volume load may surpass the heart's adaptive capacity, potentially triggering a transition from physiological remodeling to pathological cardiac changes (107). Moreover, when exercise load consistently exceeds the physiological tolerance of the body, it leads to sustained elevation of mTORC1 activity, resulting in endoplasmic reticulum (ER) homeostasis imbalance. This condition also triggers a reduction in miR-222 expression, thereby weakening its inhibitory effect on downstream Cyclin-dependent kinase inhibitor 1B (p27) and Hmbox1. This shift signifies the transition of the heart from adaptive remodeling to pathological remodeling, laying the molecular foundation for myocardial fibrosis and electrical activity abnormalities (110, 111). Therefore, quantifying these molecular biomarkers and dynamically adjusting exercise protocols based on the results ensures that cardiac remodeling remains within physiological adaptation limits, helping to prevent adverse cardiac remodeling due to overtraining. This approach forms the foundation for scientific management of athlete cardiac health.

Resistance exercise involves active muscle contractions against external loads, aiming to enhance muscular strength, endurance, or hypertrophy. This form of exercise exerts beneficial effects not only on skeletal muscle but also on myocardial structure and function (112). During resistance training, sustained muscular contraction—often accompanied by relative hypoxia—leads to a marked increase in peripheral vascular resistance. This results in acute elevation in blood pressure and significantly augments left ventricular afterload. Over time, these hemodynamic changes stimulate myocardial remodeling, characterized by increased ventricular wall thickness without substantial chamber dilation—a process defined as concentric hypertrophy (113). Research has shown that after a 24-week resistance training program, consisting of three one-hour sessions per week, participants showed an increase in left ventricular mass (LVM) accompanied by ventricular wall thickening compared to baseline. These adaptations resulted in the development of concentric cardiac hypertrophy (114). In an animal study, 12 weeks of resistance training led to progressive increases in LVM, with observed increments of 8%, 12%, and 16% in weeks 4, 8, and 12, respectively. Importantly, these structural adaptations were accompanied by improved left ventricular systolic function, whereas changes in the LVEDV remained minimal. These findings support the development of concentric hypertrophy, with morphological changes becoming more pronounced over time (115). It is noteworthy that, while substantial evidence supports the induction of concentric hypertrophy by long-term resistance training, some human studies indicate that structural myocardial changes may be minimal even under significant afterload. For instance, a study involving participants with a mean age of approximately 68 years reported no significant alterations in ventricular size or wall thickness after 16 weeks of resistance training compared with baseline measurements. This observation may be attributed to age-related decline in cardiac autonomic regulation, which could diminish the myocardium's responsiveness to sympathetic stimulation (51, 114). Mechanistically, the primary driver of ventricular wall thickening in resistance exercise-induced concentric hypertrophy is the parallel addition of sarcomeres within cardiomyocytes. This pattern contrasts with the longitudinal sarcomere elongation seen in eccentric hypertrophy associated with endurance exercise (115).

During resistance exercise, sustained pressure overload induces adaptive cardiovascular remodeling, often manifested as transient yet substantial elevations in arterial blood pressure. Studies have shown that during maximal-intensity training, such as heavy weightlifting, arterial pressures can rise markedly compared to resting values (116). While this form of pressure overload is physiological, it bears resemblance to pathological pressure overload seen in conditions such as hypertension, which can also lead to concentric hypertrophy. However, pathologically induced hypertrophy is typically accompanied by systolic and/or diastolic dysfunction, as well as asymmetric thickening of the interventricular septum and the left ventricular posterior wall (117). The morphological similarities between physiological concentric hypertrophy resulting from resistance training and pathological forms of hypertrophy may pose diagnostic challenges and risk clinical misinterpretation (Figure 1).

Exercise intensity is commonly classified as low, moderate, or high, with each level exerting distinct physiological effects on the development of PCH. Low-intensity exercise is generally defined as physical activity that maintains heart rate at 50%–60% of an individual's maximum heart rate. This level of exertion is unlikely to induce significant cardiac remodeling and thus does not typically lead to the development of PCH. It is, however, considered appropriate for older adults or individuals with limited exercise tolerance and reduced physical capacity (124).

Moderate-intensity exercise is typically defined as activity that elevates heart rate to 60%–75% of an individual's maximum. This level of exertion increases venous return and cardiac preload, promoting volume overload and consequently inducing eccentric hypertrophy—characterized primarily by ventricular chamber dilation with minimal wall thickening. Moderate-intensity exercise is widely regarded as optimal for enhancing aerobic capacity and cardiorespiratory function and is considered the most effective stimulus for physiological eccentric hypertrophy (125, 126). In a study involving 12 participants (7 males and 5 females), a year-long moderate-intensity endurance training program was implemented. Cardiac magnetic imaging (CMI) was performed every three months to assess LVM, right ventricular mass (RVM), LVEDV, and right ventricular end-diastolic volume (RVEDV). The results demonstrated progressive increases in both cardiac mass and volume over the training period, indicating the development of eccentric hypertrophy (127). Experimental studies support this notion. After 8 weeks of moderate-intensity endurance training, rats in the exercise group exhibited significant increases in left and right ventricular chamber volumes and the LVM, with minimal changes in ventricular wall thickness—indicating the development of eccentric hypertrophy (128). Similarly, Fernandes et al. reported that rats subjected to 10 weeks of moderate-intensity swimming displayed load-induced eccentric remodeling of the myocardium (126). The underlying mechanism is believed to involve enhanced myocardial protein synthesis and suppressed protein degradation, leading to increased accumulation of myofibrils and cellular organelles within cardiomyocytes. These changes contribute to the enlargement of myocardial cells and the development of eccentric hypertrophy (129, 130). Additionally, moderate-intensity exercise promotes myocardial angiogenesis, improving coronary perfusion and facilitating the delivery of oxygen and nutrients to cardiomyocytes—thereby synergistically supporting cardiac growth and remodeling (131).

High-intensity exercise is defined as an activity that raises the heart rate above 75% of the individual's maximum, typically involving short-duration, high-energy expenditure efforts. This type of exercise exerts a dual effect on the heart, inducing both adaptive and potentially maladaptive changes (132). One prominent physiological adaptation is the development of concentric hypertrophy, marked by increased left ventricular wall thickness with minimal or no change in chamber volume (7). A study conducted by the Cellular Medicine Research Institute at Newcastle University examined the impact of HIIT on cardiac structure and function in patients with type 2 diabetes. After 12 weeks of HIIT or pharmacologic intervention, patients in the HIIT group exhibited greater left ventricular wall thickening, increased end-diastolic diameter, and improved myocardial contractility and relaxation compared to the pharmacologic treatment group, indicating the induction of concentric hypertrophy by HIIT (133). High-intensity exercise places substantial demands on cardiac output, stimulating robust protein synthesis in cardiomyocytes, which facilitates cellular growth and suppresses apoptosis (134). Furthermore, this training modality enhances myocardial energy metabolism, thereby contributing to the development of PCH (26). Nevertheless, prolonged or excessive acute high-intensity exercise may lead to electrical remodeling and right ventricular diastolic dysfunction, which could predispose individuals to atrial and ventricular arrhythmias (135) (Table 3).

During exercise-induced PCH, the IGF-1/ PI3K/Akt signaling pathway plays a central regulatory role. Activation of this pathway is associated with increased myofibril number, improved stroke volume (SV), and enhanced maximal oxygen uptake (VO₂ max) (36). IGF-1, a polypeptide hormone structurally analogous to insulin, is primarily synthesized and secreted by the liver in response to growth hormone stimulation. It exerts multiple systemic effects, including the reduction of blood glucose and lipid levels (138). Studies have demonstrated that myocardial IGF-1 levels are elevated in athletes with PCH compared to those without hypertrophy, and serum IGF-1 concentrations increase following exercise, implicating IGF-1 as a key mediator in exercise-induced cardiac remodeling (139). During mechanical loading from exercise, mechanoreceptors in cardiomyocytes are activated, promoting IGF-1 binding to Insulin-like Growth Factor 1 Receptor (IGF-1R). This interaction triggers receptor autophosphorylation and subsequent recruitment of Insulin Receptor Substrate (IRS) proteins, which form a signaling complex that initiates PI3K activation (140).

The PI3K family comprises enzymes that phosphorylate phosphoinositide and are essential regulators of various cellular processes, including proliferation and apoptosis (141). In a study involving four weeks of swimming training in mice, those with reduced PI3K expression exhibited significantly attenuated PCH compared to controls, highlighting PI3K's critical role in exercise-induced cardiac remodeling (8). PI3K catalyzes the conversion of Phosphatidylinositol 4,5-bisphosphate (PIP₂) to Phosphatidylinositol (3,4,5)-trisphosphate (PIP₃) at the cell membrane. As a secondary messenger, PIP₃ facilitates the membrane recruitment of Akt and Pyruvate Dehydrogenase Kinase 1 (PDK1) (142). Akt activation requires phosphorylation at T308 by PDK1 and at S473 by Mammalian target of rapamycin protein complex 2 (mTORC2), representing a pivotal step in the downstream signaling cascade. Evidence from an 8-week swimming protocol in rats showed a marked increase in phosphorylated Akt levels in myocardial tissue compared to sedentary controls. This activation of the PI3K/Akt/mTORC signaling axis was associated with the induction of PCH in response to exercise (143).

After Akt activation, it phosphorylates Tuberous Sclerosis Complex 2 (TSC2), thereby inhibiting its suppressive effect on Ras Homolog Enriched in Brain-GTP (Rheb-GTP). This disinhibition allows Rheb-GTP to bind and activate the mTORC1 (144, 145). mTORC1 is a central serine/threonine kinase complex that phosphorylates key downstream effectors, including ribosomal protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) (146). Phosphorylated S6K1 enhances ribosomal biogenesis and protein translation, thereby increasing intracellular protein synthesis, promoting cardiomyocyte hypertrophy, and facilitating the progression of PCH (147). Xu et al. further demonstrated that mTORC1 promotes protein biosynthesis primarily through 4E-BP1 phosphorylation (148). Once phosphorylated, 4E-BP1 detaches from eukaryotic translation initiation factor 4E (eIF4E), allowing eIF4E to interact with additional initiation factors to form the translation initiation complex. This process accelerates protein synthesis and leads to an accumulation of myofibrils and organelles within myocardial cells, laying the structural foundation for PCH development (144, 149).It is noteworthy that the activation level of the IGF-1/PI3K/Akt signaling pathway in response to exercise load is influenced by gender differences. Reports indicate that during exercise-induced PCH, female athletes typically exhibit lower activation levels of the IGF-1/PI3K/Akt pathway compared to their male counterparts, though the activation in females is more sustained (150, 151). This may be due to differences in myocardial cell responses to mechanical load and hormonal stimuli between genders.

Neuregulin 1 (NRG1) is an epidermal growth factor-like protein that promotes cardiomyocyte proliferation and hypertrophy while inhibiting apoptosis, playing a critical role in cardiac development and the maintenance of cardiac function (152, 153). Studies have shown that long-term aerobic exercise increases blood shear stress, which stimulates endothelial cells in the heart to secrete NRG1. The EGF-like domain of NRG1 binds to Erythroblastic Leukemia Viral Oncogene Homolog 4 (ErbB4) on the cell membrane, promoting the formation of ErbB4/ Erythroblastic Leukemia Viral Oncogene Homolog 2 (ErbB2) heterodimers (154). This process recruits downstream molecules such as Akt to the membrane and activates them. Through the PI3K/Akt/mTORC1 signaling pathway, it promotes the biosynthesis of proteins and ribosomes, facilitating myocardial cell hypertrophy and limited proliferation, thereby contributing to the development of PCH (155, 156). Additionally, studies have shown that, compared to younger athletes, older athletes exhibit significantly reduced expression of NRG1 and lower activity of the ErbB4 receptor in myocardial cells, which impacts hypertrophy and proliferation. This reduction is likely due to aging-related decline in myocardial cell responsiveness to load stimuli (157, 158).

Glycogen synthase kinase-3 beta (GSK-3β) is a multifunctional serine/threonine kinase involved in diverse cellular signaling pathways (159, 160). Following Akt activation, phosphorylation of GSK-3β at the Ser9 residue leads to suppression of its kinase activity, thereby attenuating the degradation of Beta-catenin (β-cat). The stabilized β-catenin accumulates in the cytoplasm and subsequently translocases into the nucleus, where it interacts with transcription factors such as T-cell factor (TCF) and lymphoid enhancer-binding factor (LEF). This complex activates transcription of downstream genes including Cellular Myelocytomatosis oncogene (c-Myc) and Cyclin D1 (CCND1), thereby facilitating G1/S phase cell cycle progression and promoting cardiomyocyte growth and proliferation. This signaling cascade plays a pivotal role in exercise-induced PCH (161–163). Moreover, Akt has been shown to phosphorylate FOXO transcription factors at specific serine/threonine sites, promoting their association with 14-3-3 proteins and consequent nuclear export. This translocation suppresses the transcription of pro-apoptotic genes such as Bcl-2 interacting cell death mediator (Bim) and Fas ligand (FasL), thereby inhibiting apoptosis and contributing to the preservation of cardiomyocyte viability. Together, these mechanisms support adaptive cardiac remodeling in response to exercise stimuli (73, 164).

The biological output of the Hippo-YAP signaling pathway is primarily mediated through the transcriptional regulation of downstream target genes by Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). This pathway is critically involved in the development of exercise-induced PCH (165, 166). Under homeostatic conditions, the Hippo pathway remains constitutively active. Specifically, mammalian sterile 20-like kinases 1 and 2 (MST1/2) form a complex with Salvador homolog 1 (SAV1), which facilitates the phosphorylation and activation of large tumor suppressor kinases 1 and 2 (LATS1/2). Activated LATS1/2 subsequently phosphorylates YAP and TAZ, promoting their interaction with 14-3-3 proteins and sequestration in the cytoplasm. This cytoplasmic retention prevents YAP/TAZ from entering the nucleus and engaging in transcriptional activation of genes associated with cell proliferation and survival, thereby inhibiting cardiomyocyte growth and proliferation under non-stress conditions (167, 168).

In response to exercise-induced mechanical and biochemical cues, cardiomyocytes activate Rho-associated coiled-coil containing protein kinase (ROCK). Phosphorylated ROCK negatively regulates the Hippo pathway by inhibiting MST1/2 activity, thereby attenuating the activation of LATS1/2 kinases (169). Furthermore, exercise-induced mechanical stress, such as cardiomyocyte stretching, triggers cytoskeletal remodeling and the release of mechanosensitive signals that reduce LATS1/2 phosphorylation levels (170). As a result, the inactivation of LATS1/2 decreases phosphorylation at key regulatory sites on YAP (Ser127) and TAZ (Ser89), facilitating their nuclear translocation (171). Once translocated into the nucleus, YAP and TAZ interact with specific transcription factors to initiate the expression of target genes associated with cardiomyocyte growth and proliferation, including connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61) (172). These YAP/TAZ downstream effectors play distinct yet complementary roles in cardiac remodeling. CTGF contributes to creating a supportive extracellular environment for cardiomyocyte expansion, while CYR61 modulates cellular processes such as proliferation and survival, collectively promoting hypertrophic and proliferative responses in myocardial tissue and thereby facilitating the development of PCH (173, 174). Furthermore, exercise-induced activation of the IGF-1/PI3K/Akt signaling pathway has been reported to enable Akt to phosphorylate MST1/2 or inhibit LATS1/2 activity, resulting in decreased phosphorylation of YAP. This modulation initiates a cascade of downstream signaling events, which promotes myocardial cell growth and enhances cardiac contractility, thereby contributing to the development of PCH (84). It is important to note that with aging, the sensitivity of myocardial cells to mechanical stress gradually decreases, leading to diminished nuclear translocation of YAP. Consequently, older individuals often require higher-intensity load stimulation to induce PCH comparable to that of younger individuals (175).

Exercise, through mechanical stress and metabolic regulation, activates intracellular signaling pathways such as IGF-1/PI3K/Akt and MAPK. These pathways subsequently activate downstream transcription factors, including cAMP response element binding protein (CREB). The cascade of downstream signaling molecules triggered by these transcription factors promotes protein synthesis within myocardial cells and increases myofibril number, playing a crucial role in the development of PCH (176). CREB has been reported to bind to the promoter region of the CCAAT/enhancer-binding protein beta (C/EBPβ) gene, leading to transcriptional repression of C/EBPβ mRNA expression (177). C/EBPβ is a transcription factor known to modulate genes involved in cell proliferation and differentiation (178). Experimental data indicate that aerobic exercise reduces C/EBPβ expression in cardiac tissue. For instance, after two weeks of aerobic training, mice exhibited significant downregulation of cardiac C/EBPβ. Moreover, cardiomyocyte-specific knockout of C/EBPβ in neonatal rat models promoted cardiomyocyte hypertrophy and proliferation (131). Comparable gene expression alterations have also been documented in zebrafish, mirroring the responses observed in murine models. In particular, Molkentin and colleagues demonstrated that swimming exercise suppressed C/EBPβ expression in zebrafish hearts, thereby enhancing cardiomyocyte growth and proliferation, promoting mild PCH, and increasing cardiomyocyte numbers following targeted C/EBPβ deletion (179). Similarly, endurance exercise-induced PCH in mice was associated with reduced C/EBPβ expression (180). Collectively, these findings support the notion that exercise-mediated downregulation of C/EBPβ serves as a critical mechanism contributing to cardiomyocyte proliferation and the adaptive remodeling characteristic of PCH.

Under resting conditions, C/EBPβ suppresses the transcriptional activity of the CBP/p300-interacting trans activator with ED-rich tail 4 (CITED4) gene by directly binding to its promoter region or by recruiting transcriptional repressors such as histone deacetylases (HDACs) (13, 181). CITED4 functions as a transcriptional co-activator, interacting with co-activators like CBP/p300 to enhance the expression of downstream target genes (182). Exercise-induced downregulation of C/EBPβ expression has been shown to alleviate this repression, thereby facilitating the upregulation of CITED4. The increased expression of CITED4 subsequently promotes cardiomyocyte proliferation and hypertrophy, inhibits apoptotic signaling pathways, and contributes to the development of PCH (107, 180). Furthermore, the regulation of the IGF-1/PI3K/Akt pathway has been shown to exhibit racial differences. Compared to European populations, East Asian populations have a lower activation threshold of CITED4 under exercise load due to genetic factors, requiring only moderate-intensity exercise to induce cardiac chamber enlargement. In contrast, African populations require higher-intensity exercise to effectively downregulate C/EBP β expression and produce significant regulatory effects (183–185). These differences highlight the need for personalized exercise protocols that consider genetic background to optimize cardiac adaptive remodeling.

Mechanical stress imposed on cardiomyocytes during exercise leads to membrane depolarization, which activates voltage-gated L-type calcium channel (VGCC). This facilitates the influx of extracellular Ca²⁺, subsequently triggering ryanodine receptor (RyR) activation on the sarcoplasmic reticulum and promoting a substantial release of stored Ca²⁺ into the cytoplasm. As a result, intracellular Ca²⁺ concentrations rise markedly (186, 187). This calcium surge serves as a central initiator of the calcineurin–nuclear factor of activated T-cells (CaN/NFAT) signaling pathway (188). Ca²⁺ binds to CaM, forming a Ca²⁺/CaM complex that activates CaN, a calcium/calmodulin-dependent phosphatase. Activated CaN dephosphorylates serine residues on NFAT proteins, inducing a conformational change that reveals the nuclear localization signal (NLS). This modification enables NFAT translocation into the nucleus, where it regulates the transcription of target genes involved in cardiac remodeling and hypertrophy (189, 190).

Evidence indicates that NFAT, in cooperation with the transcription factor GATA4, binds to the promoter region of the β-myosin heavy chain (β-MHC) gene to enhance its transcriptional activity. This interaction facilitates an increase in cardiomyocyte volume while preserving contractile function, thereby contributing to adaptive cardiac remodeling without inducing fibrosis—a hallmark of exercise-induced PCH (191, 192). Moreover, atrial natriuretic peptide (ANP) and BNP are cardiac-derived peptide hormones with established roles in promoting natriuresis, diuresis, and vasodilation, thereby maintaining cardiovascular and fluid homeostasis (61, 193). Interestingly, studies have shown that nuclear-localized NFAT can bind to the promoter regions of the ANP and BNP genes and suppress their transcription. This inhibitory regulation is thought to help preserve myocardial metabolic balance and structural integrity, reducing the risk of ECM accumulation, fibrosis, and pathological remodeling under conditions of physiological stress such as exercise (194).

During exercise-induced PCH, RNA N6-methyladenosine (m6A) methylation serves as a key regulatory mechanism. This regulation involves methyltransferases, demethylases, and downstream signaling cascades, which collectively enhance protein synthesis in myocardial cells, increase myofibril number, and promote metabolic reprogramming. m⁶A methylation involves the addition of a methyl group to the nitrogen at the sixth position of adenosine residues within RNA transcripts, forming N6-methyladenosine. This epitranscriptomic modification plays a fundamental role in RNA metabolism, influencing processes such as RNA stability, splicing, translation, and degradation (195, 196).

During exercise-induced PCH, regulatory pathways such as mRNA degradation and transcriptional repression contribute to the downregulation of methyltransferase like 14 (METTL14) mRNA expression, resulting in decreased METTL14 synthesis (197). Moreover, exercise modulates METTL14 protein levels via mechanisms including translational repression and enhanced protein degradation, collectively leading to an overall reduction in m6A methylation. Notably, reduced m6A levels have been shown to facilitate the degradation of Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) mRNA through the YTH domain family protein 2 (YTHDF2) reader, thereby suppressing its expression (198). The downregulation of Phlpp2 alleviates its inhibitory effect on Akt activity, consequently activating the IGF-1/PI3K/Akt signaling pathway. This activation promotes myocardial hypertrophy and proliferation while inhibiting apoptosis, culminating in coordinated ventricular wall thickening and cardiac dilation, which supports the development of PCH (197). Furthermore, previous studies have demonstrated that Akt can inhibit the activity of GSK-3β. This inhibition reduces the phosphorylation of NFAT, enabling NFAT to expose its nuclear localization signal and translocate into the nucleus. Nuclear NFAT binds to DNA and upregulates the expression of pro-survival genes, including interleukin-2 (IL-2) and B-cell lymphoma-extra large (Bcl-xL), as well as factors related to myocardial proliferation such as CITED4. This cascade enhances myocardial protein synthesis and proliferation while suppressing apoptosis, playing a critical role in the physiological remodeling associated with PCH (188, 199).

In the context of exercise-induced PCH, RNA m⁶A methylation modification exhibits significant sex- and age-related differences in regulation. Studies have shown that, due to estrogen influence, female athletes have reduced METTL14 mRNA expression in myocardial cells at baseline, along with enhanced demethylase activity. As a result, baseline m6A methylation levels are lower in females compared to males. Through this regulatory mechanism, females are able to more effectively downregulate PHLPP2 expression after exercise, thus more efficiently activating the IGF-1/PI3K/Akt pathway to induce PCH (197)^. However, in older individuals, the downregulation of METTL14 mRNA during exercise is less pronounced, and compared to younger individuals, the overall reduction in m⁶A methylation is smaller. This limits the degradation efficiency of PHLPP2 mRNA, restricting Akt activation and downstream signal molecule expression (200). These differences in regulation suggest that females exhibit stronger metabolic adaptability, while older individuals require higher load thresholds to achieve equivalent cardiac remodeling effects as younger individuals. This finding provides molecular-level theoretical support for the development of personalized exercise programs.

Circular Uridine (circUtrn), a circular RNA associated with cardioprotective effects, is significantly upregulated in response to exercise-induced stress. CircUtrn enhances the activity of protein phosphatase 5 (PP5) by directly interacting with its catalytic domain (201). PP5, a serine/threonine phosphatase, is involved in critical cellular processes such as DNA damage repair and cell cycle regulation (202). Recent studies have demonstrated that PP5 activates downstream mammalian target of mTORC1, thereby relieving its inhibitory effect on CCND1. This promotes cardiomyocyte cell cycle re-entry, supporting myocardial repair and regeneration (203). This mechanism closely parallels the adaptive mTORC1 activation observed during PCH, enhancing cardiac reserve while mitigating pathological fibrosis. In addition, circUtrn functions as a molecular sponge for microRNA-195-5p (miR-195-5p), a pro-apoptotic microRNA known to suppress anti-apoptotic genes such as F-box and WD repeat domain-containing protein 7 (FBXW7) and Mitofusin 2 (MFN2) (204). By sequestering miR-195-5p, circUtrn alleviates its repression of FBXW7 and MFN2, thereby reducing cardiomyocyte apoptosis, promoting mitochondrial biogenesis, and enhancing energy metabolism. This multi-target regulatory mechanism aligns closely with the fundamental features of exercise-induced PCH, contributing to improved myocardial adaptability and function (205).

p27 negatively regulates cell cycle progression by inhibiting the Cyclin-dependent kinase 2 (CDK2)/Cyclin E complex, thereby blocking the G1-to-S phase transition (206). Studies have shown that miR-222 can bind to the 3ʹ untranslated region (3ʹ UTR) of p27 mRNA, suppressing its translation and leading to reduced p27 protein levels. This alleviation of CDK2/Cyclin E inhibition facilitates G1/S transition, promotes cardiomyocyte proliferation, and contributes to the enhancement of cardiac function associated with PCH (207). In addition to its role in cell cycle regulation, miR-222 also targets Hmbox1, a transcription factor that activates the Transforming Growth Factor-β (TGF-β)/Smad signaling pathway. This pathway promotes fibroblast-to-myofibroblast conversion and excessive ECM deposition, culminating in myocardial fibrosis (208). By binding to the 3ʹ UTR of Hmbox1 mRNA, miR-222 downregulates Hmbox1 expression, thereby inhibiting Transforming Growth Factor-β (TGF-β)/Smad protein (Smad) pathway activation and preventing fibrotic remodeling of the myocardium (209). Moreover, miR-222 indirectly upregulates α-myosin heavy chain (α-MHC) expression while suppressing β-MHC expression through the downregulation of p27 and Hmbox1. This shift increases the α-MHC/β-MHC ratio, thereby enhancing myocardial contractility, inhibiting myocardial fibrosis, and counteracting pathological cardiac remodeling (110).

FAO, a central pathway in myocardial energy metabolism, not only supplies energy during exercise but also modulates gene expression through its metabolic intermediates and associated signaling pathways, forming a complex regulatory network. This mechanism plays a critical role in the development of PCH, enhances exercise capacity, and delays the onset of fatigue. Upon exercise stimulation, epinephrine (EPI) binds to β-adrenergic receptors (βARs), activating adenylate cyclase (AC) and leading to the generation of cyclic adenosine monophosphate (cAMP). cAMP subsequently activates protein kinase A (PKA), a key effector in this cascade (210). Studies have shown that PKA can enhance the activity of the fatty acid transporter CD36, thereby promoting the transmembrane uptake of free fatty acids (FFAs) into cardiomyocytes (211). Once internalized, FFAs are converted into acyl-Coenzyme A (Acyl-CoA) by cytosolic acyl-CoA synthetase (ACS). Acyl-CoA is then transported into mitochondria via carnitine palmitoyl transferase 1 (CPT1), the rate-limiting enzyme of mitochondrial FAO. Within the mitochondria, Acyl-CoA undergoes β-oxidation to generate acetyl-Coenzyme A (Acetyl-CoA), as well as reduced cofactors NADH and FADH₂. These products subsequently fuel the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, supplying ATP to meet the high energy demands of cardiomyocytes (149, 150). Enhanced efficiency of this metabolic pathway is essential for supporting the increased energy requirements during PCH induced by exercise (212, 213). Additionally, during exercise-induced PCH, female athletes generally exhibit a higher degree of FAO metabolic dependency compared to male athletes. It has been reported that under the regulation of estrogen, activation of transcription factors such as PPARα in females enhances FAO capacity during exercise, which significantly distinguishes female myocardial cells from the glycolytic metabolism phenotype predominant in males (214). This metabolic difference aids in the enhanced mitochondrial biogenesis capacity of female athletes during long-term endurance exercise.

Additionally, accumulating evidence suggests that acetyl-Coenzyme A (Acetyl-CoA), a key metabolic intermediate and signaling molecule, plays an important role in the epigenetic regulation of gene expression during exercise-induced PCH. Elevated intracellular levels of Acetyl-CoA can activate histone acetyltransferases (HATs), such as p300, which catalyze the acetylation of histone H3 at lysine 9 (H3K9ac) and lysine 27 (H3K27ac). These histone modifications promote chromatin relaxation and transcriptional activation of growth-related genes, including GATA4 and Myocyte Enhancer Factor 2 (MEF2). Consequently, this process downregulates the expression of hypertrophy-related genes such as ANP and BNP, while inhibiting pro-fibrotic pathways like TGF-β. While promoting myocardial cell growth and proliferation, it also induces the development of PCH (215). Moreover, this epigenetic regulation supports cardiomyocyte growth and proliferation while simultaneously suppressing pro-fibrotic signaling pathways, including TGF-β, thereby facilitating the development of a physiological hypertrophic phenotype (197). Peroxisome proliferator-activated receptor alpha (PPARα), a nuclear transcription factor critical for FAO, is highly expressed in myocardial tissue. During exercise, Akt-mediated phosphorylation enhances the transcriptional activity of PPARα. Activated PPARα promotes the expression of key FAO enzymes such as CPT1 and medium-chain acyl-CoA dehydrogenase (MCAD), thereby accelerating mitochondrial FAO and supporting sustained ATP production in cardiomyocytes (216). This metabolic reprogramming shifts substrate preference toward fatty acids, improving energy efficiency while minimizing the accumulation of potentially toxic metabolic byproducts. Collectively, these molecular and metabolic adaptations contribute to the emergence of a PCH phenotype characterized by cardiomyocyte hypertrophy and proliferation, enhanced cardiac output, and resistance to pathological fibrosis.

During exercise-induced PCH, multiple molecular pathways and metabolic regulatory networks are involved in glucose metabolism, supporting the energy supply and adaptive growth of myocardial cells, as well as enhancing exercise capacity. Glucose transporter type 4 (GLUT4), localized in intracellular vesicles, is the principal glucose transporter in cardiomyocytes (217). Wende et al. demonstrated that GLUT4 plays a pivotal role in the cardiac metabolic adaptation to increased hemodynamic load during exercise (218). Notably, activation of Akt signaling during exercise leads to the phosphorylation of Akt substrate of 160kDa (AS160), a Rab GTPase-activating protein. Phosphorylated AS160 loses its GAP activity, allowing GLUT4-containing vesicles to translocate to the plasma membrane. This translocation markedly increases glucose uptake by cardiomyocytes, thereby boosting ATP production to meet the immediate energy demands of the heart under exercise-induced stress (219). Additionally, Akt has been shown to inhibit the activity of GSK-3β, thereby limiting its phosphorylation of glycogen synthase (GS), resulting in the dephosphorylation and activation of GS. This process promotes the conversion of glucose into glycogen, providing a metabolic foundation for myocardial cell proliferation and hypertrophy. It also plays a positive role in protein synthesis and the delay of fatigue onset (220, 221).

Notably, Akt also promotes mitochondrial function by phosphorylating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a master regulator of mitochondrial biogenesis. This phosphorylation event enhances the transcription of genes involved in mitochondrial DNA replication and oxidative metabolism, thereby improving mitochondrial efficiency and facilitating the complete oxidation of glycogen-derived substrates such as pyruvate. These processes provide sustained energy support, which is essential for the development of PCH (222, 223). In addition to mitochondrial adaptations, glucose metabolism is tightly regulated during PCH. Under normal physiological conditions, Hmbox1 acts as a negative regulator of glucose metabolism by inhibiting the expression of the glucokinase gene (Gck). However, in a swimming-induced model of PCH, downregulation of Hmbox1 expression was observed during exercise, which led to the upregulation of Gck. Glucokinase catalyzes the phosphorylation of glucose to glucose-6-phosphate (G6P), the first and rate-limiting step in glycolysis. This enhances intracellular glucose uptake and utilization, ensuring a steady supply of energy substrates for cardiomyocyte metabolism. Such metabolic reprogramming is a hallmark of exercise-induced PCH and contributes to its adaptive, non-pathological nature (224) (Figure 2).