αvβ3- and α5β1-integrin blockade inhibits myogenic constriction of skeletal muscle resistance arterioles

2005 ◽  
Vol 289 (1) ◽  
pp. H322-H329 ◽  
Author(s):  
Luis A. Martinez-Lemus ◽  
Tracy Crow ◽  
Michael J. Davis ◽  
Gerald A. Meininger

In isolated resistance arterioles with spontaneous tone, ligation of α4β1- and α5β1-integrins induces vasoconstriction whereas ligation of αvβ3-integrin induces vasodilation. However, whether integrins directly participate in myogenic constriction to pressure elevation is not known. To answer this question, isolated rat skeletal muscle arterioles were exposed to step increments in pressure in the absence or presence of peptides and function-blocking antibodies known to bind α4β1-, α5β1-, or αvβ3-integrins while vessel diameter was continually monitored. Myogenic constriction, as assessed by the ability of isolated arterioles to reduce their diameter in response to two consecutive increments in intraluminal pressure (90–110 and 110–130 cmH2O), was not affected by treatment with any of the control peptides (RAD, LEV), a control antibody (anti-rat major histocompatibility complex), an α4β1-integrin-binding peptide (LDV), or an anti-α4-integrin antibody. In contrast, α5β1-integrin blockade with either anti-α5- or anti-β1-integrin antibody caused a significant inhibition of myogenic constriction. Also, both RGD peptide and anti-β3-integrin antibody inhibited myogenic constriction. These results indicate that α5β1- and αvβ3-integrins are necessary for myogenic constriction and further suggest that integrins are part of the mechanosensory apparatus responsible for the ability of vascular smooth muscle cells to detect and/or respond to changes in intraluminal pressure.

1991 ◽  
Vol 260 (1) ◽  
pp. H130-H135 ◽  
Author(s):  
J. C. Falcone ◽  
M. J. Davis ◽  
G. A. Meininger

The goal of this study was to determine whether the endothelium played a role in the myogenic response of skeletal muscle arterioles. First-order arterioles (n = 15) were isolated from the rat cremaster muscle and cannulated for in vitro study. The development of spontaneous tone reduced the diameter of the isolated arterioles from 166.7 +/- 7.6 microns to 89.2 +/- 7.2 microns. The arterioles were exposed to step changes in intraluminal pressure over a range of 10–170 cmH2O and had no flow through their lumen. The vessels exhibited active constriction to step increases or active dilation to step decreases in pressure (50–150 cmH2O). At 90 cmH2O, arterioles dilated by 89.2 +/- 6.0% in response to the endothelium-dependent vasodilator acetylcholine (10(-6) M; ACh) and 89.6 +/- 10.9% in response to endothelium-independent dilator adenosine (10(-4) M; Ado). The endothelium was physically denuded by rubbing the vessel lumen. After denudation, the arteriolar dilation to ACh was abolished, whereas the dilation to Ado was unaltered. The absence of endothelium was verified by electron microscopy. Basal tone and the response to changes in pressure were not significantly different from endothelium-intact vessels. These studies indicate that the endothelium is not responsible for myogenic activity or development of spontaneous tone in skeletal muscle arterioles.


2002 ◽  
Vol 92 (3) ◽  
pp. 1145-1151 ◽  
Author(s):  
Cristine L. Heaps ◽  
Douglas K. Bowles

Hindlimb unweighting (HLU) has been shown to alter myogenic tone distinctly in arterioles isolated from skeletal muscles composed predominantly of fast-twitch (white gastrocnemius) compared with slow-twitch (soleus) fibers. Based on these findings, we hypothesized that HLU would alter myogenic tone differently in arterioles isolated from distinct fiber-type regions within a single skeletal muscle. We further hypothesized that alterations in myogenic tone would be associated with alterations in voltage-gated Ca2+ channel current (VGCC) density of arteriolar smooth muscle. After 14 days of HLU or weight bearing (control), first-order arterioles were isolated from both fast-twitch and mixed fiber-type regions of the gastrocnemius muscle, cannulated, and pressurized at 90 cmH2O. Mixed gastrocnemius arterioles of HLU rats demonstrated increased spontaneous tone [43 ± 5% (HLU) vs. 27 ± 4% (control) of possible constriction] and an approximately twofold enhanced myogenic response when exposed to step changes in intraluminal pressure (10–130 cmH2O) compared with control rats. In contrast, fast-twitch gastrocnemius arterioles of HLU rats demonstrated similar levels of spontaneous tone [6 ± 2% (HLU) vs. 6 ± 2% (control)] and myogenic reactivity to control rats. Neither KCl-induced contractile responses (10–50 mM KCl) nor VGCC density was significantly different between mixed gastrocnemius arterioles of HLU and control rats. These results suggest that HLU produces diverse adaptations in myogenic reactivity of arterioles isolated from different fiber-type regions of a single skeletal muscle. Furthermore, alterations in myogenic responses were not attributable to altered VGCC density.


2017 ◽  
Author(s):  
François Singh ◽  
Joffrey Zoll ◽  
Urs Duthaler ◽  
Anne-Laure Charles ◽  
Gilles Laverny ◽  
...  

AbstractStatins are generally well-tolerated, but can induce myopathy. Statins are associated with impaired expression of PGC-1β in human and rat skeletal muscle. The current study was performed to investigate the relation between PGC-1β expression and function and statin-associated myopathy. In WT mice, atorvastatin impaired mitochondrial function in glycolytic, but not in oxidative muscle. In PGC-1β KO mice, atorvastatin induced a shift from oxidative type IIA to glycolytic type IIB myofibers mainly in oxidative muscle and mitochondrial dysfunction was observed in both muscle types. In glycolytic muscle of WT and KO mice and in oxidative muscle of KO mice, atorvastatin suppressed mitochondrial proliferation and oxidative defense, leading to apoptosis. In contrast, mitochondrial function was maintained or improved and apoptosis decreased by atorvastatin in oxidative muscle of WT mice. In conclusion, PGC-1β has an important role in preventing damage to oxidative muscle in the presence of a mitochondrial toxicant such as atorvastatin.


1999 ◽  
Vol 86 (4) ◽  
pp. 1178-1184 ◽  
Author(s):  
Michael D. Delp

The purpose of the present study was to determine whether hindlimb unloading of rats alters vasoconstrictor and myogenic responsiveness of skeletal muscle arterioles. After either 2 wk of hindlimb unloading (HU) or cage control (C), second-order arterioles were isolated from the white portion of gastrocnemius (WG; C: n = 9, HU: n = 10) or soleus (Sol; C: n = 9, HU: n = 10) muscles and cannulated with two micropipettes connected to reservoir systems for in vitro study. Intraluminal pressure was set at 60 cmH2O. The arterioles were exposed to step changes in intraluminal pressure ranging from 20 to 140 cmH2O to determine myogenic responsiveness and to KCl (10–100 mM) and norepinephrine (10−9–10−4M) to determine vasoconstrictor responsiveness. Although maximal diameter of WG arterioles was not different between C (185 ± 12 μm) and HU (191 ± 14 μm) rats, WG arterioles from HU rats developed less spontaneous tone (C: 33 ± 5%, HU 20 ±3%), were unable to maintain myogenic tone at pressures from 140 to 100 cmH2O, and were less sensitive to the vasoconstrictor effects of KCl and norepinephrine (as indicated by a higher agonist concentration that produced 50% of maximal vasoconstrictor response). In contrast, maximal diameter of Sol arterioles from HU rats (117 ± 12 μm) was smaller than that in C rats (148 ± 14 μm). However, the development of spontaneous tone (C: 30 ± 4%, HU: 36 ± 5%), myogenic activity, and the responsiveness to vasoconstrictor agonists were not different between Sol arterioles from C and HU rats. These results indicate that hindlimb unloading diminishes the myogenic autoregulatory and contractile responsiveness of arterioles from muscle composed of type IIB fibers and suggest that the compromised ability to elevate vascular resistance after exposure to microgravity may be related to these vascular alterations. In addition, hindlimb unloading appears to induce vascular remodeling of arterioles from muscle composed of type I fibers, as indicated by the decrease in maximal diameter of arterioles from Sol muscle.


1993 ◽  
Vol 265 (1) ◽  
pp. E135-E144 ◽  
Author(s):  
L. B. Tadros ◽  
P. M. Taylor ◽  
M. J. Rennie

Glutamine transport was studied in preconfluent monolayered, mononucleated myoblasts (4 days old) and in fused, multinucleated, differentiated myotubes (10 days old), both prepared from neonatal rat skeletal muscle. The initial (60 s) rate of 50 microM glutamine uptake in myoblasts and myotubes was stereospecific, saturable, and largely (80%) Na+ dependent. At glutamine concentrations of 0.01–1 mM, Na(+)-dependent uptake showed saturation kinetics: in myoblasts, the Michaelis constant (Km) was 197 +/- 38 microM, maximum velocity (Vmax) was 1,165 +/- 60 pmol.min-1.mg protein-1; in myotubes, Km was 174 +/- 51 microM and Vmax was 1,435 +/- 47 pmol.min-1.mg protein-1. The Na(+)-dependent glutamine uptake was Li+ tolerant in both myoblasts and myotubes. The Na(+)-dependent uptake of 50 microM L-[3H]glutamine was investigated in the presence of various amino acids at 0.01–10 mM. Histidine and asparagine competitively inhibited glutamine uptake, but inhibition by serine was noncompetitive; glutamate, arginine, leucine, and 2-aminobicyclo(2,2,1)heptane-2-carboxylate (BCH) had no significant inhibitory effects; 2-(methyl-amino)isobutyrate (MeAIB) caused a small but significant inhibition. In parallel with a stimulation of glucose transport, addition of insulin stimulated Na(+)-dependent glutamine uptake within 1 h by a maximum of 27% in myoblasts and 42% in myotubes (half-maximal stimulation at 0.3 nM insulin). Glucagon had no effect. Kinetic analysis revealed that the insulin-stimulated increase in glutamine transport was due to a Vmax effect, which was cycloheximide inhibitable. The insulin-stimulated increase was Li+ tolerant and not inhibited by MeAIB or cysteine at 1 mM. The results indicate that the predominant glutamine transporter of neonatal rat skeletal muscle cells in primary tissue culture in System Nm. System Nm also appears to be the major insulin-sensitive glutamine transport component in skeletal muscle. Primary muscle culture appears to be a useful preparation for studying glutamine transport and its regulation.


2000 ◽  
Vol 89 (6) ◽  
pp. 2227-2234 ◽  
Author(s):  
Michael P. Massett ◽  
Akos Koller ◽  
Gabor Kaley

The purpose of this study was to investigate the mechanism underlying arteriolar responses to hyperosmolality and to determine the effects of daily exercise on this response. Dilator responses were measured in isolated, cannulated, and pressurized skeletal muscle arterioles. Osmolality was increased from ∼290 to 330 mosmol/kgH2O by adding glucose, sucrose, or mannitol to the superfusion solution. All three compounds elicited similar changes in vessel diameter, suggesting that this response was due to changes in osmolality. Responses to glucose were abolished by endothelium removal but were not altered in endothelium-intact vessels by superfusion with the nitric oxide synthase inhibitor N ω-nitro-l-arginine or the cyclooxygenase inhibitor indomethacin. In endothelium-intact arterioles, responses to glucose superfusion with the ATP-sensitive potassium (KATP) channel inhibitor glibenclamide; however, intraluminal perfusion with glibenclamide nearly abolished the responses to glucose and mannitol. Intraluminal administration of glucose elicited a significantly greater dilation than extraluminal glucose. The response to intraluminal glucose was also inhibited by intraluminal glibenclamide. Four weeks of daily exercise did not significantly alter the responses to hyperosmolality in gracilis or soleus muscle arterioles. These data demonstrate that physiological increases in intraluminal osmolality dilate rat skeletal muscle arterioles via activation of endothelial KATP channels; however, this endothelium-dependent response is not augmented by daily exercise.


2014 ◽  
Vol 472 ◽  
pp. 792-800 ◽  
Author(s):  
Gui Jun Dong ◽  
Chen Xi Lv ◽  
Ke Feng Li

To research ultrastructure changes of rat skeletal muscle in the process of repetition eccentric exercise, Wistar rats were divided into normal control group, one eccentric exercise group, repeated eccentric exercise group. The ultrastructure and proteome changes made by downhill run and repetitive downhill run after a week in rats were observed in instant, 24h, 48h, 72h and 168h after one and repeated bout of exercise rats. The results showed that the most serious injuries of sarcomere in 48 hours after exercise, sarcomere disordered or disappeared, Z-line fractured and myofilament decomposed. From 24h to 48h, mitochondria was severely damaged, which structure gradually restored within 72 hours, the muscle fiber reconstructed, but mitochondrial number, structure and function had not yet been fully restored, the muscle cells in aerobic capacity have not yet fully been restored. At the same time, the injury severity of repeated exercise group was palliative compared to that of the first exercise, which may be related to recovery rate of mitochondrial damage. Therefore, repetitive motion can change the mitochondria's own repair speed, stimulate muscle to adapt the density of exercise, and reduce the extent of skeletal muscle micro-injury. Repeated eccentric exercise may promote key enzyme expression of energy metabolism and energy supply for damage cell, accelerate skeletal muscle contraction protein degradation and cell swallow, and scavenge free radicals and slow inflammatory reaction during 24-48h to speed up the skeletal muscle damage repair. Keywords: Eccentric Exercise, Repetitive Exercise, Skeletal Muscle, Ultrastructure, Peoteome


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