scholarly journals Stimulation of Alpha1-Adrenergic Receptor Ameliorates Cellular Functions of Multiorgans beyond Vasomotion through PPARδ

PPAR Research ◽  
2020 ◽  
Vol 2020 ◽  
pp. 1-21
Author(s):  
Yong-Jik Lee ◽  
Hyun Soo Kim ◽  
Hong Seog Seo ◽  
Jin Oh Na ◽  
You-Na Jang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Biological Effects ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Spontaneously Hypertensive ◽  
Atp Production ◽  
Multiple Organs ◽  
Organ Specific

Cells can shift their metabolism between glycolysis and oxidative phosphorylation to enact their cell fate program in response to external signals. Widely distributed α1-adrenergic receptors (ARs) are physiologically stimulated during exercise, were reported to associate with the activating energetic AMPK pathway, and are expected to have biological effects beyond their hemodynamic effects. To investigate the effects and mechanism of AR stimulation on the physiology of the whole body, various in vitro and in vivo experiments were conducted using the AR agonist midodrine, 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxy-ethyl]-acetamide. The expression of various biomarkers involved in ATP production was estimated through Western blotting, reverse transcription polymerase chain reaction, oxygen consumption rate, enzyme-linked immunosorbent assay (ELISA), fluorescence staining, and Oil red O staining in several cell lines (skeletal muscle, cardiac muscle, liver, macrophage, vascular endothelial, and adipose cells). In spontaneously hypertensive rats, blood pressure, blood analysis, organ-specific biomarkers, and general biomolecules related to ATP production were measured with Western blot analysis, immunohistochemistry, ELISA, and echocardiography. Pharmacological activation of α1-adrenergic receptors in C2C12 skeletal muscle cells promoted mitochondrial oxidative phosphorylation and ATP production by increasing the expression of catabolic molecules, including PPARδ, AMPK, and PGC-1α, through cytosolic calcium signaling and increased GLUT4 expression, as seen in exercise. It also activated those energetic molecules and mitochondrial oxidative phosphorylation with cardiomyocytes, endothelial cells, adipocytes, macrophages, and hepatic cells and affected their relevant cell-specific biological functions. All of those effects occurred around 3 h (and peaked 6 h) after midodrine treatment. In spontaneously hypertensive rats, α1-adrenergic receptor stimulation affected mitochondrial oxidative phosphorylation and ATP production by activating PPARδ, AMPK, and PGC-1α and the relevant biologic functions of multiple organs, suggesting organ crosstalk. The treatment lowered blood pressure, fat and body weight, cholesterol levels, and inflammatory activity; increased ATP content and insulin sensitivity in skeletal muscles; and increased cardiac contractile function without exercise training. These results suggest that the activation of α1-adrenergic receptor stimulates energetic reprogramming via PPARδ that increases mitochondrial oxidative phosphorylation and has healthy and organ-specific biological effects in multiple organs, including skeletal muscle, beyond its vasomotion effect. In addition, the action mechanism of α1-adrenergic receptor may be mainly exerted via PPARδ.

scholarly journals Mitochondrial oxidative phosphorylation complexes exist in the sarcolemma of skeletal muscle

BMB Reports ◽  
2016 ◽  
Vol 49 (2) ◽  
pp. 116-121 ◽  
Author(s):  
Hyun Lee ◽  
Seung-Hyeob Kim ◽  
Jae-Seon Lee ◽  
Yun-Hee Yang ◽  
Jwa-Min Nam ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Oxidative Phosphorylation

P6277The impact of exercise training in combination with statin use on skeletal muscle mitochondrial oxidative phosphorylation and metabolomics in obese rats

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
I Urbaneck ◽  
F Lorenz ◽  
I Materzok ◽  
L Maletzki ◽  
M Pietzner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cytochrome C ◽  
Exercise Training ◽  
Oxidative Phosphorylation ◽  
Atp Synthase ◽  
Statin Treatment ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Complex Iv ◽  
Obese Rats ◽  
Statin Use

Abstract Background Exercise training (ET) and statin treatment both alter skeletal muscle function. Purpose We investigated the effects of a combined exercise and statin use on skeletal muscle mitochondrial oxidative phosphorylation (OxPhos) and metabolic alterations in obese rats. Methods Eight-week-old male Wistar rats were used. A total of 14 animals received standard chow, while 46 rats were fed a high-fat diet (HFD) for 20 weeks. After 8 weeks, the rats were randomized into 6 groups: sedentary (n=8), ET (n=6), sedentary with HFD (n=11), ET with HFD (n=11), statin with HFD (n=13) and ET with HFD and statins (n=11). Simvastatin (10mg/d/kg) was added to the drinking water. ET was performed for 12 weeks, 5 days/week for 1 h/day at 18 m/min in a motorized running wheel. OxPhos was assessed by complex-specific antibodies and targeted metabolomics using the Biocrates p180 kit. All experiments were done on frozen samples of the M. gastrocnemicus. An ANOVA with fixed effects for diet, exercise, statin treatment and statin-exercise interaction was used to identify significantly different metabolites. Results Statin use was associated with significantly lower cholesterol levels, but did not affect exercise duration and intensity compared to none-use. In sedentary animals, HFD increased OxPhos complex II (succinate dehydrogenase), complex IV (cytochrome-c-oxidase) and V (ATP synthase) while statin treatment diminished this increase in all complexes. HFD increased complex IV independent of statin treatment but had no effect on complex II and V in ET rats. Complex IV was increased due to ET only in HFD fed rats compared to rats on normal chow but decreased in contrast to sedentary animals on a HFD. With regards to metabolomics, we found 57 metabolites which were influenced by HFD while no metabolites were identified with a significant effect for ET. A significant statin-exercise interaction was found for three lysophosphatidylcholines (lysoPC a C26.0, lysoPC a C26.1, lysoPC a C24.0), one phosphatidylcholine (PC aa C42.6) and one sphingomyelin (SM C16.1). HFD decreased the concentration of all mentioned metabolites compared to standard chow fed animals. Likewise, ET increased the concentration of metabolites compared to sedentary animals on HFD. Statin treatment led to an increase, while statin in combination with ET did not rescue this effect. Conclusion HFD induced severely impaired skeletal muscle OxPhos independent of ET and statin treatment. Our findings suggest a limiting rate of NADH production in the tricarboxylic acid cycle as a potential mechanism. However, ET prevented the increase in cytochrome-c-oxidation while statins blocked the HFD induced increase in ATP synthase. Our metabolomics results imply that future research should consider the lipotoxic effects of a HFD when assessing skeletal muscle alterations due to ET or statins. Of particular interest could be the 5 metabolites that have been shown to be impacted by a statin-exercise interaction.

Cardiovascular effects of dobutamine during exercise in dogs

1989 ◽  
Vol 257 (3) ◽  
pp. H954-H960
Author(s):  
G. C. Haidet ◽  
T. I. Musch ◽  
D. B. Friedman ◽  
G. A. Ordway
Keyword(s):  
Skeletal Muscle ◽  
Heart Rate ◽  
Blood Flow ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Maximal Exercise ◽  
Cardiovascular Effects ◽  
Receptor Reserve ◽  
Concomitant Reduction ◽  
Stimulation Of

To test the hypothesis that stimulation of adrenergic receptors in the heart is maximal during maximal exercise, and to determine whether generalized stimulation of adrenergic receptors during strenuous exercise produces significant alterations in the normal regional distribution of blood flow that occurs during exercise, we evaluated the cardiovascular effects of the infusion of dobutamine (40 micrograms.kg-1.min-1) in mongrel dogs during treadmill running. During maximal exercise, the dobutamine infusion resulted in a significant (P less than 0.05) increase in heart rate. Exercise capacity, total body O2 consumption (VO2), and maximal arteriovenous O2 difference, however, each were reduced during the infusion of this drug. A concomitant reduction in maximal blood flow to locomotive skeletal muscle occurred. The infusion of dobutamine also resulted in an increase in heart rate at a strenuous level of submaximal exercise. However, unlike during maximal exercise, VO2 was unchanged. Blood flow to locomotive skeletal muscle increased, and there was a concomitant reduction in arteriovenous O2 difference. Blood flow reductions that normally occur in splanchnic circulations during strenuous and during maximal exercise were generally somewhat attenuated during the infusion of this drug. Thus, dobutamine, a sympathomimetic agent, produces significant cardiovascular effects when infused in high doses during exercise. Our results demonstrate that beta-adrenergic receptor reserve exists in the heart during maximal exercise in dogs. In addition, the peripheral responses that occur during the infusion of the drug provide additional evidence that different degrees of adrenergic receptor reserve normally appear to be present within different regional circulations during strenuous and during maximal exercise.

Human tissue adrenergic receptors are not predictive of responses to epinephrine in vivo

1989 ◽  
Vol 256 (5) ◽  
pp. E600-E609
Author(s):  
S. B. Liggett ◽  
S. D. Shah ◽  
P. E. Cryer
Keyword(s):  
Skeletal Muscle ◽  
Adenylate Cyclase ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Interindividual Variation ◽  
Mononuclear Leukocytes ◽  
Circulating Cells ◽  
Beta 2 ◽  
Sufficient Magnitude

To test the hypotheses that adrenergic receptor and adenylate cyclase characteristics of easily accessible circulating cells reflect those of relatively inaccessible extravascular catecholamine target tissues in a subtype-specific fashion and that these characteristics predict responses to catecholamines in vivo, we studied 22 normal humans. Adrenergic receptors and their linked adenylate cyclase systems were measured in mononuclear leukocytes (MNL; beta 2), platelets (alpha 2), skeletal muscle membranes (beta 2), and fat cells (B1 and alpha 2) and compared with the responses to stepped, intravenous epinephrine infusions in vivo. MNL beta 2-adrenergic receptor densities (but not antagonist affinities) were correlated (r = 0.627; P less than 0.01) with skeletal muscle beta 2-adrenergic densities. However, other adrenergic receptor characteristics and basal and maximally stimulated adenosine 3',5'-cyclic monophosphate (cAMP) contents of MNL and all adrenergic receptor characteristics and cAMP contents of platelets were unrelated to the corresponding measurements in skeletal muscle and fat. Furthermore, there were no consistent relationships between tissue adrenergic receptor-adenylate cyclase characteristics and the chronotropic, diastolic depressor, lipolytic, ketogenic, glycemic, or glycogenolytic-glycolytic responses to epinephrine in vivo. Thus the data support the hypothesis that adrenergic receptor densities on circulating cells reflect those of extravascular target tissues in a subtype-specific fashion. On the other hand, the data do not support the hypothesis that physiological interindividual variation of adrenergic receptor characteristics is of sufficient magnitude to alter sensitivity to epinephrine in vivo.

scholarly journals Heat and α1-adrenergic responsiveness in human skeletal muscle feed arteries: the role of nitric oxide

2012 ◽  
Vol 113 (11) ◽  
pp. 1690-1698 ◽  
Author(s):  
Stephen J. Ives ◽  
Robert H. I. Andtbacka ◽  
Sun Hyung Kwon ◽  
Yan-Ting Shiu ◽  
Ting Ruan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Human Skeletal Muscle ◽  
Bovine Endothelial Cells ◽  
No Bioavailability ◽  
Feed Arteries ◽  
Skeletal Muscle Feed Arteries

Increased local temperature exerts a sympatholytic effect on human skeletal muscle feed arteries. We hypothesized that this attenuated α1-adrenergic receptor responsiveness may be due to a temperature-induced increase in nitric oxide (NO) bioavailability, thereby reducing the impact of the α1-adrenergic receptor agonist phenylephrine (PE). Thirteen human skeletal muscle feed arteries were harvested, and wire myography was used to generate PE concentration-response curves at 37°C and 39°C, with and without the NO synthase (NOS) inhibitor NG-monomethyl-l-arginine (l-NMMA). A subset of arteries ( n = 4) were exposed to 37°C or 39°C, and the protein content of endothelial NOS (eNOS) and α1-adrenergic receptors was determined by Western blot analysis. Additionally, cultured bovine endothelial cells were exposed to static or shear stress conditions at 37°C and 39°C and assayed for eNOS activation (phosphorylation at Ser1177), eNOS expression, and NO metabolites [nitrate + nitrite (NOx)]. Maximal PE-induced vasocontraction (PEmax) was lower at 39°C than at 37°C [39 ± 10 vs. 84 ± 30% maximal response to 100 mM KCl (KClmax)]. NO blockade restored vasocontraction at 39°C to that achieved at 37°C (80 ± 26% KClmax). Western blot analysis of the feed arteries revealed that heating increased eNOS protein, but not α1-adrenergic receptors. Heating of bovine endothelial cells resulted in greater shear stress-induced eNOS activation and NOx production. Together, these data reveal for the first time that, in human skeletal muscle feed arteries, NO blockade can restore the heat-attenuated α1-adrenergic receptor-mediated vasocontraction and implicate endothelium-derived NO bioavailability as a major contributor to heat-induced sympatholysis. Consequently, these findings highlight the important role of vasodilators in modulating the vascular response to vasoconstrictors.

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