Molecular insights of exercise therapy in disease prevention and treatment

Abstract

Despite substantial evidence emphasizing the pleiotropic benefits of exercise for the prevention and treatment of various diseases, the underlying biological mechanisms have not been fully elucidated. Several exercise benefits have been attributed to signaling molecules that are released in response to exercise by different tissues such as skeletal muscle, cardiac muscle, adipose, and liver tissue. These signaling molecules, which are collectively termed exerkines, form a heterogenous group of bioactive substances, mediating inter-organ crosstalk as well as structural and functional tissue adaption. Numerous scientific endeavors have focused on identifying and characterizing new biological mediators with such properties. Additionally, some investigations have focused on the molecular targets of exerkines and the cellular signaling cascades that trigger adaption processes. A detailed understanding of the tissue-specific downstream effects of exerkines is crucial to harness the health-related benefits mediated by exercise and improve targeted exercise programs in health and disease. Herein, we review the current in vivo evidence on exerkine-induced signal transduction across multiple target tissues and highlight the preventive and therapeutic value of exerkine signaling in various diseases. By emphasizing different aspects of exerkine research, we provide a comprehensive overview of (i) the molecular underpinnings of exerkine secretion, (ii) the receptor-dependent and receptor-independent signaling cascades mediating tissue adaption, and (iii) the clinical implications of these mechanisms in disease prevention and treatment.

Fig. 1

Molecular exercise therapy: mode of action and clinical implications of exercise-induced signaling molecules (exerkines). The effect of exerkines on the human organism can broadly be divided into exerkine kinetics and exerkine dynamics. During acute exercise, numerous exerkines are secreted in an autocrine, paracrine and/or endocrine manner. In the case of endocrine secretion, these exerkines are distributed throughout the human organisms, making them available to distinct target tissues. The intensity and duration of an exerkine effect is dictated by the exerkine concentration over time (area under the curve, AUC), which, in case of endocrine secretion, can be quantified as plasma exerkine levels. For autocrine and paracrine secretion, microdialysis or other techniques for isolation of extracellular fluids allow precise quantification of tissue-specific exerkine concentrations and determination of exerkine concentration-time curves. Of note, exerkines might also be subject to metabolization and elimination via distinct routes. Once exerkines are secreted, they interact with target cells in a receptor-dependent or receptor-independent manner. For receptor-dependent interactions, the effect on target cells depends on the precise characteristics of the target receptor and the exerkine–receptor interaction. The intrinsic activity of an exerkine (agonism vs. antagonism), its affinity to the target receptor, and the receptor density on target cells dictate dose-response relationships for exerkine-exerkine receptor pairs that determine the potency and efficacy of an exerkine. For receptor-independent mechanisms, passive diffusion across the cell membrane, transmembrane transporters, and extracellular vesicle (EV)-mediated uptake of exerkines have been described. Once exerkines have entered the intracellular space, they can trigger signal transduction and subsequent adaption processes in a distinct fashion. These molecular characteristics as well as inter-individual differences in health status and lifestyle habits (e.g., diet, exercise, sleeping behavior) determine the magnitude of tissue adaption. Transferring mechanistic knowledge on exerkine kinetics and exerkine dynamics into disease context has promising clinical implications, e.g., in disease prevention, targeted exercise therapy and the development of novel, exercise-inspired pharmaceutics (i.e., exercise mimetics). Created with BioRender.com

Fig. 2

Signaling mechanisms of exerkines. Exerkines may mediate cellular adaption via direct action on target cells (direct exerkine effect) or by stimulating other cell types to release bioactive compounds such as cytokines (indirect exerkine effect). Both, direct and indirect effects require the interaction of exerkines with target cells as an initial step. a, b In the case of direct exerkine effects, the cellular adaptions occur within the target cells themselves. c, d For indirect exerkine effects, the targeted cells induce adaption processes in other cell types. Interaction of exerkines with target cells can occur in a receptor-dependent (a, c) or a receptor-independent manner (b, d). Extracellular vesicles and nitric oxide are prime examples of receptor-independent exerkine mechanisms. Created with BioRender.com

Fig. 3

Overview of exerkine receptors and downstream signaling pathways investigated in animal studies. Autocrine, paracrine, and endocrine mobilization makes exerkines available for exerkine receptors localized on distinct target cells including myocytes (a), cardiomyocytes (b), lymphatic endothelial cells (b), osteocytes (c), white adipocytes (d), neurons (e), and macrophages (f). Binding of exerkines to their target receptor triggers tissue-specific signaling cascades and adaption processes with potential therapeutic effects in different diseases. Downstream mediators of exerkine signaling that were investigated in vivo are highlighted in green. APLNR apelin receptor, CX3XR1 C-X3-C motif chemokine receptor 1, IL-15Rα Interleukin-15 receptor α, IL-15 Interleukin 15, TGF-βR2 transforming growth factor β receptor 2, GFRA2 Glial cell line derived neurotrophic factor family receptor α 2, RET REarranged during Transfection, NTN Neurturin, TRKB Tropomyosin-related kinase B, BDNF Brain-derived neurotrophic factor, NRG1 Neuregulin 1, ERBB2/ERBB4 Erb-B2 Receptor Tyrosine Kinase 2/ Erb-B2 Receptor Tyrosine Kinase 4, VEGFR3 Vascular endothelial growth factor receptor 3, VEGF Vascular endothelial growth factor, IGF-1 Insulin-like growth factor 1, NRP2 Neuropilin 2, RCN2 Reticulocalbin 2, FSTL1 Follistatin-like 1, DIP2A Disco-interacting protein 2 homolog A, HSL hormone sensitive lipase, MRGPRD Mas-related G protein-coupled receptor type D, L-BAIBA β-aminoisobutyric acid, HCAR1 Hydroxycarboxylic acid receptor 1, FGFR1 Fibroblast growth factor receptor 1, KLB Co-receptor β-Klotho, FGF21 Fibroblast growth factor 21, GPR35 G protein-coupled receptor 35, KYNA Kynurenic acid, GFRAL Glial cell line derived neurotrophic factor family Receptor α Like, GDF15 Growth differentiation factor 15, TIE-2 Tyrosine-protein kinase receptor TEK, ANGPT1 Angiopoietin 1, SUCNR1 Succinate receptor 1. Created with BioRender.com

Fig. 4

Overview of exerkine receptors investigated in human trials. Due to methodological and ethical constraints of mechanistic exercise studies in humans, exerkine receptor activation is harder to investigate in humans compared to animals. Exerkine target tissues that have been investigated in humans comprise cardiac muscle tissue and epicardial adipose tissue (a), neutrophils, natural killer cells, and dendritic cells (b), and visceral adipose tissue (c). IL-6R interleukin-6 receptor, IL-8R interleukin-8 receptor, NK cell natural killer cell, DC dendritic cell, IL-6R interleukin 6 receptor, IL-8R interleukin 8 receptor. Created with BioRender.com

Fig. 5

Schematic illustration of the exerkine research continuum. Owing to technological advances, remarkable progress is being made in identifying new exerkines and describing their kinetics in response to an acute bout of exercise (left section of the figure). To uncover exerkine-mediated tissue adaptions, some studies have identified molecular targets of exerkines (e.g., exerkine receptors) that transduce these effects (central section of the figure). However, less attention is devoted to potential further target tissues that also express these molecular targets. In-depth characterization of global exerkine dynamics—i.e., the interaction of exerkines with different target tissues—holds the potential to advance our understanding of the pan-tissue benefits mediated by exercise (right section of the figure). Created with BioRender.com