Purinergic signaling as a new mechanism underlying physical exercise benefits: a narrative review

Cardoso, Andréia Machado; Silverio, Mauro Nicollas Oliveira; Maciel, Sarah Franco Vieira de Oliveira

doi:10.1007/s11302-021-09816-4

Cited by 8 publications

(10 citation statements)

References 162 publications

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“…Even circulating adenosine and nucleotides may stimulate hepatic glycogenolysis [ 41 ]. This may involve purinergic signaling via G-protein-coupled receptors (GPCRs) activated by adenosine or nucleotides [ 42 , 43 , 44 , 45 ]. Speculatively, endocannabinoids might also influence hepatic glucose metabolism via GPCRs [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

Studies in Rats of Combined Muscle and Liver Perfusion and of Muscle Extract Indicate That Contractions Release a Muscle Hormone Directly Enhancing Hepatic Glycogenolysis

Han

Holst

Galbo

2022

JPM

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Background: Established neuroendocrine signals do not sufficiently account for the exercise-induced increase in glucose production. Using an innovative, yet classical cross-circulation procedure, we studied whether contracting muscle produces a factor that directly stimulates hepatic glycogenolysis. Methods: Isolated rat hindquarters were perfused in series with isolated livers. Results: Stimulation of the sciatic nerve of one or both legs resulted in an increase in force, which rapidly waned. During one-legged contractions, hepatic glucose production increased initially (from −0.9 ± 0.5 (mean ± SE) to 3.3 ± 0.7 µmol/min, p < 0.05). The peak did not differ significantly from that seen after 20 nM of epinephrine (5.1 ± 1.2 µmol/min, p > 0.05). In response to two-legged contractions, the increase in hepatic glucose production (to 5.4 ± 1.3 µmol/min) was higher (p < 0.05) and lasted longer than that seen during one-legged contractions. During contractions, peak hepatic glucose output exceeded concomitant hepatic lactate uptake (p < 0.05), and glucose output decreased to basal levels, while lactate uptake rose to a plateau. Furthermore, in separate experiments an increase in lactate supply to isolated perfused livers increased lactate uptake, but not glucose output. In intact rats, intra-arterial injection of extract made from mixed leg muscle elicited a prolonged increase (p < 0.05) in plasma glucose concentration (from 5.2 ± 0.1 mM to 8.3 ± 1.5 mM). In perfused livers, muscle extract increased glucose output dose dependently. Fractionation by chromatography of the extract showed that the active substance had a MW below 2000. Conclusion: This study provides evidence that contracting skeletal muscle may produce a hormone with a MW below 2000, which enhances hepatic glycogenolysis according to energy needs. Further chemical characterization is warranted.

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Section: Resultsmentioning

confidence: 99%

Studies in Rats of Combined Muscle and Liver Perfusion and of Muscle Extract Indicate That Contractions Release a Muscle Hormone Directly Enhancing Hepatic Glycogenolysis

Han

Holst

Galbo

2022

JPM

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“…Few studies have followed the signaling trail upstream from these proteomic changes to the small molecule metabolites measured by metabolomics that initiate the protein changes. Recent metabolomics studies have underscored the importance of metabolites such as ATP as both substrates for biochemical reactions and as signaling molecules that bind G‐protein coupled receptors (GPCRs), ion channels, and many membrane solute carriers (SLCs) and transporters that initiate the acute metabolic response to exercise 23,37,46 . ATP signaling has also been shown to play a key role in developmental disorders such as autism spectrum disorder (ASD), 47 neuroprotection and neuroregeneration, 48 mental health, 49 and neurodegenerative disorders 50 …”

Section: Discussionmentioning

confidence: 99%

“…Recent metabolomics studies have underscored the importance of metabolites such as ATP both substrates for biochemical reactions and as molecules that bind G-protein coupled receptors (GPCRs), ion channels, and many membrane solute carriers (SLCs) and transporters that initiate the acute metabolic response to exercise. 23,37,46 ATP signaling has also been shown to play a key role in developmental disorders such as autism spectrum disorder (ASD), 47 neuroprotection and neuroregeneration, 48 mental health, 49 and neurodegenerative disorders. ATP is released as a neuromodulator and coneurotransmitter from every synapse in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…21 These studies add to the growing body of evidence that many of the multisystem effects of exercise are traceable to primary and adaptive changes in mitochondrial function called the mitochondrial nexus 22 and to its regulation by ATP. 23 No studies have yet examined the metabolomic effects of acute endurance exercise in cerebrospinal fluid.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cerebrospinal fluid and plasma metabolomics of acute endurance exercise

Schön

Naviaux

et al. 2022

The FASEB Journal

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Metabolomics has emerged as a powerful new tool in precision medicine. No studies have yet been published on the metabolomic changes in cerebrospinal fluid (CSF) produced by acute endurance exercise. CSF and plasma were collected from 19 young active adults (13 males and 6 females) before and 60 min after a 90‐min monitored outdoor run. The median age, BMI, and VO2 max of subjects was 25 years (IQR 22–31), 23.2 kg/m2 (IQR 21.7–24.5), and 47 ml/kg/min (IQR 38–51), respectively. Targeted, broad‐spectrum metabolomics was performed by liquid chromatography, tandem mass spectrometry (LC–MS/MS). In the CSF, purines and pyrimidines accounted for 32% of the metabolic impact after acute endurance exercise. Branch chain amino acids, amino acid neurotransmitters, fatty acid oxidation, phospholipids, and Krebs cycle metabolites traceable to mitochondrial function accounted for another 52% of the changes. A narrow but important channel of metabolic communication was identified between the brain and body by correlation network analysis. By comparing these results to previous work in experimental animal models, we found that over 80% of the changes in the CSF correlated with a cascade of mitochondrial and metabolic changes produced by ATP signaling. ATP is released as a co‐neurotransmitter and neuromodulator at every synapse studied to date. By regulating brain mitochondrial function, ATP release was identified as an early step in the kinetic cascade of layered benefits produced by endurance exercise.

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“…For instance, exercise activates purinergic signaling (ATP, ADP, adenosine, related receptors, and enzymes) ( Moritz et al, 2021 ). The purinergic system has relevance in inflammatory response and, particularly, in the shift from the pro-inflammatory response to acute, intense exercise to the anti-inflammatory response associated with chronic exercise ( Cardoso et al, 2021 ). Exercise improves immune functions via the stimulation of the neuroendocrine secretion of catecholamines and the activation of their signaling ( Simpson et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Impact of 12-Week Moderate-Intensity Aerobic Training on Inflammasome Complex Activation in Elderly Women

et al. 2022

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Aging often associates with a chronic low-grade inflammatory status that can be consequent to the activation of Toll-like receptors (TLRs) and the downstream NLR family pyrin domain containing 3 (NLRP3) inflammasome and causes a chronic secretion of pro-inflammatory cytokines. Since exercise has known anti-inflammatory effects, we investigated the effect of Nordic walking training on inflammasome activation and downstream effectors in elderly women. A population of elderly women was divided into EXP (n = 29) that completed 12 weeks of the moderate-intensity aerobic training program and CTRL (n = 29), performing no activity. Blood samples were taken before and after the first (T1-pre and T1-post, respectively) and last (T2-pre and T2-post, respectively) exercise unit. Inflammasome activation status was assessed by whole blood NLRP3 and TLR4 expression by RT-qPCR. Serum levels of IL-1β, IL-6, TNFα, and IL-18 cytokines were assayed by multiplex fluorescent beads-based immunoassays or ELISA. NLRP3 and TLR4 levels were reduced 2 folds between T1-pre and T2-pre and induced at T2-post, compared to T2-pre, by 2.6- and 2.9-fold, respectively. A single exercise bout elicited a 1. 38-, 1. 5-, and 1.36-fold rise of IL-1β, TNFα, and IL-6 concentration, respectively, although not significant, at the beginning of the training (T1-pre vs. T1-post), a 1.4-fold decrease for IL-1β and TNFα at the end of the training (T1-pre vs. T2-pre), and a 2-, 1.8- and 1.26-fold increase after the last exercise session (T2-pre vs. T2-post) for the three cytokines. When stratifying the population based on BMI in normal weight (NW) and overweight (OW), NLRP3 and TLR4 expression was affected only in NW. As for inflammatory cytokines, IL-1β was modulated in NW at the beginning of the training, whereas in OW at the end of the training; for TNFα, this time-dependent modulation was significant only in OW. Applied aerobic training affected the resting expression of inflammasome constituents (NLRP3 and TLR4) and levels of downstream effectors (IL-1β, TNFα, and IL-6). However, at the end of the program, participants acquire an acute inflammatory response to exercise that was absent at baseline. Future studies would have to define the molecular mechanisms associated with, and how to potentiate, the exercise-associated inflammatory response.

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Purinergic signaling as a new mechanism underlying physical exercise benefits: a narrative review

Cited by 8 publications

References 162 publications

Studies in Rats of Combined Muscle and Liver Perfusion and of Muscle Extract Indicate That Contractions Release a Muscle Hormone Directly Enhancing Hepatic Glycogenolysis

Studies in Rats of Combined Muscle and Liver Perfusion and of Muscle Extract Indicate That Contractions Release a Muscle Hormone Directly Enhancing Hepatic Glycogenolysis

Cerebrospinal fluid and plasma metabolomics of acute endurance exercise

Impact of 12-Week Moderate-Intensity Aerobic Training on Inflammasome Complex Activation in Elderly Women

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