A farnesyltransferase inhibitor attenuated β-adrenergic  receptor downregulation in rat skeletal muscle

Farnesylation represents an essential posttranslational modification of several well-defined proteins implicated in the homologous desensitization of the β-adrenergic receptor (β-ADR). The following study examined the effect of a novel farnesyltransferase inhibitor, BMS-191563, on agonist-mediated β-ADR downregulation in skeletal muscle. Female Sprague-Dawley rats were treated for 12 days with the β2-adrenergic agonist clenbuterol (4 mg/kg) with or without the concurrent administration of BMS-191563 (2 mg · kg−1 · day−1). Clenbuterol promoted gastrocnemius muscle hypertrophy, whereas the soleus muscle was unaffected. Total β-ADR density was decreased by 45 and 40% in the soleus and medial gastrocnemius (MG), respectively, after clenbuterol treatment. BMS-191563 treatment did not prevent clenbuterol-stimulated MG hypertrophy, but markedly attenuated β-ADR downregulation in both muscle types. This latter effect in the soleus muscle was not associated with the inhibition of Ras farnesylation. Likewise, in rat cardiac fibroblasts, isoproterenol-mediated decrease of total β-ADR density was abrogated by the prior treatment with BMS-191563. Collectively, these data demonstrate that the mechanism(s) implicated in agonist-mediated β-ADR downregulation was sensitive to BMS-191563, thereby suggesting the involvement of farnesylated proteins.

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Chronic β-blockade increases skeletal muscle β-adrenergicreceptor density and enhances contractile force

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.2.459 ◽

1997 ◽

Vol 83 (2) ◽

pp. 459-465 ◽

Cited By ~ 11

Author(s):

René J. L. Murphy ◽

Phillip F. Gardiner ◽

Guy Rousseau ◽

Michel Bouvier ◽

Louise Béliveau

Keyword(s):

Skeletal Muscle ◽

Adrenergic Receptor ◽

Contractile Force ◽

Medial Gastrocnemius ◽

Receptor Density ◽

Sprague Dawley ◽

Oxidative Potential ◽

Sprague Dawley Rats ◽

Adrenergic Antagonist ◽

Contractile Forces

Murphy, René J. L., Phillip F. Gardiner, Guy Rousseau, Michel Bouvier, and Louise Béliveau. Chronic β-blockade increases skeletal muscle β-adrenergic-receptor density and enhances contractile force. J. Appl. Physiol.83(2): 459–465, 1997.—The effects of a chronic 14-day administration of a selective β2-adrenergic-receptor antagonist (ICI-118551) on skeletal muscle were evaluated in female Sprague-Dawley rats. Chronic ICI-118551 treatment did not modify muscle mass, oxidative potential, or protein concentration of the medial gastrocnemius muscle, suggesting that maintenance of these skeletal muscle characteristics is not dependent on β2-adrenergic-receptor stimulation. However, the drug treatment increased β-adrenergic-receptor density of the lateral gastrocnemius (42%) and caused an increase in specific (g/g) isometric in situ contractile forces of the medial gastrocnemius [twitch, 56%; tetanic (200 Hz), 28%]. The elevated contractile forces observed after a chronic treatment with ICI-118551 were completely abolished when the β2-adrenergic antagonist was also administered acutely before measurement of contractile forces, suggesting that this response is β2-adrenergic-receptor dependent. Possible mechanisms for the increased forces were studied. Caffeine administration potentiated twitch forces but had little effect on tetanic force in control animals. Administration of dibutyryl adenosine 3′,5′-cyclic monophosphate in control animals also resulted in small increases of twitch force but did not modify tetanic forces. We conclude that increases in β-adrenergic-receptor density and the stimulation of the receptors by endogenous catecholamines appear to be responsible for increased contractile forces but that the mechanism remains to be demonstrated.

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Skeletal muscle Ca2+ flux and catabolic response during sepsis

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.3.r487 ◽

1993 ◽

Vol 265 (3) ◽

pp. R487-R493 ◽

Cited By ~ 2

Author(s):

J. Bhattacharyya ◽

K. D. Thompson ◽

M. M. Sayeed

Keyword(s):

Skeletal Muscle ◽

Soleus Muscle ◽

Experimental Sepsis ◽

Protein Catabolism ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Rat Soleus Muscle ◽

Catabolic Response ◽

Net Protein

Membrane Ca2+ flux and net protein catabolism were studied in the skeletal muscle during experimental sepsis. Sterilized rat fecal pellets with (septic) or without (sterile) gram-negative bacteria, Escherichia coli [10(2) colony-forming units (cfu)] and Bacteroides fragilis (2 x 10(3) cfu), were implanted into the abdomens of male Sprague-Dawley rats (110-120 g). Septic and sterile rats were febrile and hyperlactacidemic on day 1 postimplantation. These responses subsided by day 2 in sterile but not septic rats. Initial Ca2+ flux, estimated from measurements of 45Ca uptake by soleus muscles in vitro, was elevated on day 1 in both sterile and septic rats and on day 2 and 3 in septic rats only. The septic rat soleus muscle showed a significantly increased net protein catabolic response (measured as tyrosine release by soleus muscle, in vitro) over that found in muscles of sterile rats on day 1-3 postimplantation. The increase in Ca2+ flux in septic (day 1-3 postimplantation) and sterile (day 1 only) rats was abolished when the rats were treated with the calcium channel blocker diltiazem. In unoperated control rat soleus muscles the Ca2+ ionophore, ionomycin, concomitantly caused an increase in Ca2+ flux and net protein catabolism. Overall, the present study suggested that altered cellular Ca2+ regulation plays a role in the net protein catabolic response in the skeletal muscle during sepsis.

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REDD2 expression in rat skeletal muscle correlates with nutrient-induced activation of mTORC1: responses to aging, immobilization, and remobilization

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00341.2014 ◽

2015 ◽

Vol 308 (2) ◽

pp. E122-E129 ◽

Cited By ~ 17

Author(s):

Andrew R. Kelleher ◽

Suzette L. Pereira ◽

Leonard S. Jefferson ◽

Scot R. Kimball

Keyword(s):

Skeletal Muscle ◽

Mrna Expression ◽

Muscle Mass ◽

Soleus Muscle ◽

Sprague Dawley ◽

Age Related ◽

Sprague Dawley Rats ◽

Mtorc1 Signaling ◽

Elevated Expression ◽

Old Rats

In a previous study (Kelleher AR, Kimball SR, Dennis MD, Schilder RJ, and Jefferson LS. Am J Physiol Endocrinol Metab 304: E229–236, 2013.), we observed a rapid (i.e., 1–3 days) immobilization-induced repression of mechanistic target of rapamycin complex 1 (mTORC1) signaling in hindlimb skeletal muscle of young (2-mo-old) rats that was associated with elevated expression of regulated in development and DNA-damage response (REDD) 1 and REDD2. The present study extends that observation to include an assessment of those parameters in soleus muscle of the immobilized hindlimb of various-aged rats as well as in response to remobilization. Male Sprague-Dawley rats aged 2, 9, and 18 mo were subjected to unilateral hindlimb immobilization for 7 days, whereas one group of the 9-mo-old animals underwent 7 days of remobilization. Soleus muscle mass-to-body mass ratio declined with age, with the loss of muscle mass following hindlimb immobilization being inversely proportional to age. Compared with 2-mo-old rats, the older rats exhibited reduced mTORC1 signaling in the nonimmobilized limb in association with elevated REDD2, but not REDD1, mRNA expression. In the 2-mo-old rats, 7 days of hindlimb immobilization attenuated mTORC1 signaling and induced REDD2, but not REDD1, mRNA expression. In contrast, hindlimb immobilization did not further attenuate the age-related reduction in mTORC1 signaling nor further enhance the age-related induction of REDD2 mRNA expression in 9- and 18-mo-old rats. Across ages, REDD1 mRNA was not impacted by immobilization. Finally, remobilization elevated mTORC1 signaling and lowered REDD2 mRNA expression, with no impact on REDD1 gene expression. In conclusion, changes in mTORC1 signaling associated with aging, immobilization, and remobilization were inversely proportional to alterations in REDD2 mRNA expression.

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Trafficking of dietary oleic, linolenic, and stearic acids in fasted or fed lean rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.278.6.e1124 ◽

2000 ◽

Vol 278 (6) ◽

pp. E1124-E1132 ◽

Cited By ~ 35

Author(s):

Daniel H. Bessesen ◽

S. Holly Vensor ◽

Matthew R. Jackman

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Stearic Acid ◽

Dietary Fat ◽

Medial Gastrocnemius ◽

Sprague Dawley ◽

Fed State ◽

Liquid Meal ◽

Fasted State ◽

Sprague Dawley Rats

Increasing evidence supports the notion that there are significant differences in the health effects of diets enriched in saturated, as opposed to monounsaturated or polyunsaturated fat. However, the current understanding of how these types of fat differ in their handling by relevant tissues is incomplete. To examine the effects of fat type and nutritional status on the metabolic fate of dietary fat, we administered 14C-labeled oleic, linolenic, or stearic acid with a small liquid meal to male Sprague-Dawley rats previously fasted for 15 h (fasted) or previously fed ad libitum (fed).14CO2 production was measured for 8 h after tracer administration. The 14C content of gastrointestinal tract, serum, liver, skeletal muscle (soleus, lateral, and medial gastrocnemius), and adipose tissue (omental, retroperitoneal, and epididymal) was measured at six time points (2, 4, 8, 24, and 48 h and 10 days) after tracer administration. Plasma levels of glucose, insulin, and triglyceride were also measured. Oxidation of stearic acid was significantly less than that of either linolenic or oleic acid in both the fed and fasted states. This reduction was in part explained by a greater retention of stearic acid within skeletal muscle and liver. Oxidation of oleate and stearate were significantly lower in the fed state than in the fasted state. In the fasted state, liver and skeletal muscle were quantitatively more important than adipose tissue in the uptake of dietary fat tracers during the immediate postprandial period. In contrast, adipose tissue was quantitatively more important than skeletal muscle or liver in the fed state. The movement of carbons derived from dietary fat between tissues is a complex time-dependent process, which varies in response to the type of fat ingested and the metabolic state of the organism.

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Effects of Exercise Intensity on PGC-1α, PPAR-γ, and Insulin Resistance in Skeletal Muscle of High Fat Diet-fed Sprague-Dawley Rats

Journal of the Korean Society of Food Science and Nutrition ◽

10.3746/jkfn.2014.43.7.963 ◽

2014 ◽

Vol 43 (7) ◽

pp. 963-971

Author(s):

Hyun-Lyung Jung ◽

Ho-Youl Kang

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Exercise Intensity ◽

High Fat Diet ◽

Sprague Dawley ◽

High Fat ◽

Ppar Γ ◽

Sprague Dawley Rats

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Methomyl induced effect on fortilin and S100A1 in serum and cardiac tissue: Potential biomarkers of toxicity

Human & Experimental Toxicology ◽

10.1177/0960327118814153 ◽

2018 ◽

Vol 38 (3) ◽

pp. 371-377

Author(s):

SD Nusair ◽

AN Joukhan ◽

AH Bani Rashaid ◽

AM Rababa’h

Keyword(s):

Toxic Effect ◽

Cardiac Tissue ◽

Cardiac Fibroblasts ◽

Study Group ◽

Sprague Dawley ◽

Cardiac Tissues ◽

Sprague Dawley Rats ◽

Cervical Dislocation ◽

Potential Biomarkers

Methomyl toxicity has been reported as a cause of several accidental and suicidal fatalities. The study is evaluating the effect of lethal methomyl toxicity on fortilin and S100A1 in serum and cardiac tissues. Adult 96 female Sprague-Dawley rats were divided equally into a control (euthanized by cervical dislocation) and a study group (overdosed with methomyl). The levels of fortilin and S100A1 in serum were measured antemortem (to establish the basal levels in serum) and postmortem (to evaluate changes after methomyl exposure) using enzyme-linked immunoassay. S100A1 was immunostained in sections from cardiac tissues. Both proteins in the control were not significantly different ( p > 0.05) compared with the antemortem levels. On the contrast, both biomarkers levels in the intoxicated group were remarkably higher ( p < 0.001) than the control and the antemortem levels. Ventricular tissues from the intoxicated rats presented depleted S100A1 immunostain in cardiomyocytes localized mainly in the epicardium with deeply stained adjacent cardiac fibroblasts. The cardiomyocytes were damaged with a prominent loss of striations compared to normal cardiac tissues from the control. The present outcomes explain to a certain degree the potential toxic effect of methomyl poisoning on the cardiac tissue. Both proteins could be added to the currently available battery of markers for assessing methomyl toxicity.

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Effects of Endurance Exercise and High-Fat Diet on Insulin Resistance and Ceramide Contents of Skeletal Muscle in Sprague-Dawley Rats

Korean Diabetes Journal ◽

10.4093/kdj.2010.34.4.244 ◽

2010 ◽

Vol 34 (4) ◽

pp. 244 ◽

Cited By ~ 9

Author(s):

Hyun Lyung Jung ◽

Ho Youl Kang

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Endurance Exercise ◽

High Fat Diet ◽

Sprague Dawley ◽

High Fat ◽

Sprague Dawley Rats

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Effect of low-potassium diet on rat exercise hyperthermia and heatstroke mortality

Journal of Applied Physiology ◽

10.1152/jappl.1981.51.1.8 ◽

1981 ◽

Vol 51 (1) ◽

pp. 8-13 ◽

Cited By ~ 13

Author(s):

R. W. Hubbard ◽

M. Mager ◽

W. D. Bowers ◽

I. Leav ◽

G. Angoff ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Weight ◽

Plasma Potassium ◽

Heat Illness ◽

Sprague Dawley ◽

Heat Gain ◽

Sprague Dawley Rats ◽

Low Potassium ◽

Work Done ◽

Low K

A total of 182 male Sprague-Dawley rats weighing 250–300 g were fed either a control (n = 122) diet for 32 days. The diets contained either 125 or 8 meq potassium/kg, respectively. Rats fed the low-K diet gained weight at only one-third the rate of controls (1.7 vs. 5.2 g/day), and their skeletal muscle and plasma potassium levels were reduced by 28 and 47%, respectively. When run to exhaustion at either 15 or 20 degrees C, low K+-fed rats accomplished less than one-half of the work done by the controls (26 vs. 53 kg. m) but exhibited a markedly greater rate of heat gain per kilogram-meter of work than controls (0.12 vs. 0.05 degrees C)ambient temperature of 20 degrees C, the rats of the low-K+ group despite large differences in body weight (-25%), run time temperature and twice (33 vs 17%) the mortality rate of the controls. Postexercise increases in circulating potassium (less than 90%) of heat-injured rats raised the plasma levels of low K+-fed rats to normal (5.9 +/- 2.2 meq/l). These results appear to characterize the existence of an insidious and, therefore, undocumented form of fatal exertion-induced heat illness.

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Chronic intermittent hypoxia alters NE reactivity and mechanics of skeletal muscle resistance arteries

Journal of Applied Physiology ◽

10.1152/japplphysiol.00994.2005 ◽

2006 ◽

Vol 100 (4) ◽

pp. 1117-1123 ◽

Cited By ~ 51

Author(s):

Shane A. Phillips ◽

E. B. Olson ◽

Julian H. Lombard ◽

Barbara J. Morgan

Keyword(s):

Skeletal Muscle ◽

Intermittent Hypoxia ◽

Chronic Intermittent Hypoxia ◽

Physiological Salt Solution ◽

Ang Ii ◽

Sprague Dawley ◽

Resistance Arteries ◽

Sprague Dawley Rats ◽

Resting Tone ◽

Wall Distensibility

Although arterial dilator reactivity is severely impaired during exposure of animals to chronic intermittent hypoxia (CIH), few studies have characterized vasoconstrictor responsiveness in resistance arteries of this model of sleep-disordered breathing. Sprague-Dawley rats were exposed to CIH (10% inspired O2 fraction for 1 min at 4-min intervals; 12 h/day) for 14 days. Control rats were housed under normoxic conditions. Diameters of isolated gracilis muscle resistance arteries (GA; 120–150 μm) were measured by television microscopy before and during exposure to norepinephrine (NE) and angiotensin II (ANG II) and at various intraluminal pressures between 20 and 140 mmHg in normal and Ca2+-free physiological salt solution. There was no difference in the ability of GA to constrict in response to ANG II ( P = 0.42; not significant; 10−10–10−7 M). However, resting tone, myogenic activation, and vasoconstrictor responses to NE ( P < 0.001; 10−9–10−6 M) were reduced in CIH vs. controls. Treatment of rats with the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol; 1 mM) in the drinking water restored myogenic responses and NE-induced constrictions of CIH rats, suggesting that elevated superoxide production during exposure to CIH attenuates vasoconstrictor responsiveness to NE and myogenic activation in skeletal muscle resistance arteries. CIH also leads to an increased stiffness and reduced vessel wall distensibility that were not correctable with oral tempol treatment.

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