An overview of the multi-dimensional mechanisms of exercise-regulated hormones and growth factors in cardiac physiological adaptation

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  FIGURE 1. Hormonal and growth factor regulation underlying exercise-induced myocardial proliferation and growth. Exercise stimulates the secretion of key hormones and growth factors, including IGF-1, HGF, testosterone, NRG1, and triiodothyronine (T3), which bind to their cognate receptors to activate downstream PI3K/AKT and MEK/ERK1/2 signaling cascades. These pathways collectively orchestrate cardiomyocyte proliferation and hypertrophic growth. Concomitantly, exercise induces paracrine VEGF secretion from cardiomyocytes, which binds to endothelial cell surface receptors to initiate Notch signaling. This intercellular crosstalk promotes endothelial NRG1 release, which together with circulatory NRG1, amplifies ErbB-mediated signaling in cardiomyocytes, thereby establishing a coordinated microenvironment for adaptive cardiac adaptation. IGF-1, insulin-like growth factor-1; IRS1, insulin receptor substrates 1; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; ERKs, extracellular signal-regulated kinases; MEK, mitogen-activated protein kinase; NRG1, neuregulin-1; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor.

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  FIGURE 2. Molecular mechanisms of exercise-induced cardiovascular and lymphatic angiogenesis. Exercise elevates circulating hepatocyte growth factor (HGF) and norepinephrine (NE) levels while stimulating cardiomyocyte-derived vascular endothelial growth factor (VEGF) secretion. HGF binds to c-Met receptors on endothelial cells, facilitating their proliferation and migration. Concurrently, NE and VEGF engage β3-adrenergic receptors (β3-AR) and VEGFR2, respectively, activating the PI3K/AKT/eNOS/NO signaling axis to orchestrate coronary angiogenesis. Furthermore, VEGF interacts with VEGFR3 on lymphatic endothelial cells, upregulating the lymphangiogenic markers LYVE-1 and podoplanin, thereby establishing a dual regulatory network of coordinated vascular and lymphatic adaptation. PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; eNOS, endothelial nitric oxide synthase; NO, nitric oxide.

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  FIGURE 3. Molecular mechanisms of exercise-induced mitochondrial adaptation and metabolic optimization. Exercise upregulates the cardiac expression of NE, IGF-1, and APN. NE engagesβ3-AR to activate the eNOS/NO signaling axis, subsequently amplifying the expression of PGC-1α. Concurrently, IGF-1 and APN stimulate the activation of PGC-1α through their respective receptors. This transcriptional coactivator orchestrates mitochondrial reprogramming by synergizing with PPARα and ERRs to enhance fatty acid β-oxidation, while also collaborating with NRF-1 and ERRs to upregulate the expression of Tfam. This coordinated regulation drives mitochondrial DNA transcription and biogenesis, and consequently energy substrate optimization and enhanced oxidative capacity.NE, norepinephrine; IGF-1, insulin-like growth factor-1; APN, adiponectin; β3-AR, β3-adrenergic receptors; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1α; ERRs, estrogen-related receptors; NRF-1, nuclear respiratory factor-1; Tfam, mitochondrial transcription factor A.

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  FIGURE 4. Molecular mechanisms of exercise-induced cardiac anti-fibrotic effects. Exercise induces the cardiac upregulation of testosterone, HGF, FGF21, ANP, and BNP, which collectively suppress fibrogenesis via inhibition of the TGFβ1/Smad pathway in cardiac fibroblasts. Testosterone attenuates collagen synthesis through two mechanisms: (1) Suppression of TGFβ1/Smad signaling and (2) NO-mediated inhibition of Ca2+/CaMKII. HGF antagonizes downstream effectors of TGFβ1, including CTGF, preventing ECM deposition. FGF21 upregulates EGR1, which represses collagen and TGF-β1 expression. ANP/BNP signaling through GCA receptors inhibits calcineurin/NFAT, NHE-1, and TGFβ1/Smad cascades, establishing a multi-targeted anti-fibrotic regulatory network.HGF, hepatocyte growth factor; FGF21, fibroblast growth factor 21; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; TGFβ1,Transforming growth factor-β1; NO, nitric oxide; CaMKII, calmodulin-dependent protein kinase II; CTGF, connective tissue growth factor; ECM, extracellular matrix; EGR1, early growth response protein 1; GCA, guanylyl cyclase-A; NHE-1, sodium-hydrogen exchanger 1

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  FIGURE 5. Multidimensional mechanism of exercise induced physiological hypertrophy of the heart. Exercise first promotes the secretion of catecholamines and increases the mechanical stress of the heart through the sympathetic adrenal medullary axis during the acute phase. Catecholamines inhibit the conversion of thyroid hormone T4 to T3 and suppress free IGF-1 by increasing the concentration of IGFBP1. Simultaneously, catecholamines act together with increased mechanical stress to promote the secretion of natriuretic peptides. Catecholamines can also increase mitochondrial energy metabolism and vascular proliferation in the acute phase. During the adaptation period of exercise, the concentration of catecholamines decreases, while concentrations of NRG1, T3, testosterone, IGF-1, VEGF, and FGF21 begin to increase, and FGF21 targets the regulation of adiponectin secretion. IGF-1 may stimulate an increase in VEGF. Finally, NRG1, T3, testosterone, and IGF-1 synergistically activate the PI3K/AKT and MAPK/ERK signaling pathways in cardiomyocytes, which synergistically activate mTOR signaling to promote the synthesis of myocardial fibers and activation of satellite cells. IGF-1 synergistically…