Abstract 355: Increasing Muscle Mass Improves Vascular Function In Obese Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Shuiqing Qiu ◽  
James Mintz ◽  
Christina Salet ◽  
Nitirut Nernpermpisooth ◽  
David Fulton ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Vascular Function ◽  
Muscle Growth ◽  
Gluteus Maximus ◽  
Mesenteric Arteries ◽  
Negative Regulator ◽  
Muscle Size ◽  
Obese Mice ◽  
Fiber Size ◽  
Oxide Synthase

Exercise improves endothelial function in obese patients. Salutatory effects of exercise include increases in muscle size and quality, reduction in fat mass and alterations of the plasma milieu. The relationships between these changes and improvements in vascular function are poorly defined. Hypothesis Increasing muscle mass by deletion of muscle growth negative regulator myostatin, improves vascular function in mesenteric arteries from obese db/db mice. Myostatin deletion increased muscle mass in both lean (gastrocnemius 57.93%, gluteus maximus 60.95%, triceps 57.64%) and obese mice (gastrocnemius 79.64%, gluteus maximus 112.32%, triceps 103.61%). Myostatin deletion increased muscle fiber size in lean and obese mice (p< 0.05) but had no significant effects on adipocyte size in obese mice. Fasting glucose, HbA1c and glucose tolerance were improved in obese myostatin null mice. Obese mice demonstrated superoxide-mediated impairment of ACh-induced vasodilation compared to lean mice. Deletion of myostatin in obese mice improved ACh-induced vasodilation in mesenteric arteries without effects in lean mice. This improvement was blunted by L-NAME. PGI 2 and EDHF mediated vasodilation were preserved in obese mice, and unaffected by myostatin deletion. Treatment with sepiapterin (a precursor of the nitric oxide synthase cofactor tetrahydrobiopoterin) restored impairment of vasodilation in obese mice, and this improvement was blocked by L-NAME. Taken together, these data suggested that increasing muscle mass by deletion of myostatin improved NO not PGI 2 or EDHF mediated vasodilation in obese mice.

Abstract 296: Elevated Nox1 in the Endothelium Determines Oxidant Load Obesity and is Reduced with Increases in Muscle Mass

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Shuiqing Qiu ◽  
James Mintz ◽  
Christina Salet ◽  
Weihong Han ◽  
Yunchao Su ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Vascular Function ◽  
Cardiovascular Health ◽  
Oxidant Stress ◽  
Muscle Growth ◽  
Gluteus Maximus ◽  
Oxidase Inhibitor ◽  
Mesenteric Arteries ◽  
Negative Regulator ◽  
Obese Mice

Increases in muscle mass, as observed with exercise, are positive influences of cardiovascular health. Recent studies from our lab have shown that increased muscle mass via deletion of myostatin improves vasodilation but the underlying mechanisms are unknown. Improving insulin resistance has been shown to improve oxidant stress, specifically via expression of NOX1. Hypothesis: Increasing muscle mass by deletion of muscle growth negative regulator myostatin, improves vascular function in mesenteric arteries from obese db/db mice via reducing NOX-mediated oxidant stress. Myostatin deletion increased muscle mass in both lean (gastrocnemius 57.93%, gluteus maximus 60.95%) and obese mice (gastrocnemius 79.64%, gluteus maximus 112.32%). Fasting glucose, HbA1c and glucose tolerance are improved in obese myostatin null mice. Obese mice demonstrate superoxide-mediated impairment of acetylcholine (Ach)-induced vasodilation compared to lean mice. Deletion of myostatin in obese mice improved Ach-induced vasodilation in mesenteric arteries without effects in lean mice. This improvement was blunted by L-NAME. PGI2 and EDHF mediated vasodilation were unaffected by obesity or myostatin deletion. Treatment with sepiapterin (1х10 -6 mol/L, a precursor of the nitric oxide synthase cofactor tetrahydrobiopoterin) or GKT(1х10 -6 mol/L, NADPH oxidase inhibitor) restored impaired vasodilation in obese mice. Elevated oxidized DNA was observed in the endothelium of obese mesenteric arteries, and this elevation was blunted by myostatin deletion. NOX1 expression was increased in the endothelium of obese mice mesenteric arteries, which was reversed by myostatin deletion. Taken together, these data suggest that increasing muscle mass by deletion of myostatin improves NO-mediated vasodilation in obese mice; this vasodilation improvement is mediated by down regulation of NOX1in the endothelium.

Abstract 470: Increasing Muscle Mass As A Therapeutic Target For The Cardiometabolic Syndrome

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
David Stepp ◽  
Shuiqing Qiu ◽  
James D Mintz ◽  
David Fulton
Keyword(s):  
Glucose Tolerance ◽  
Muscle Mass ◽  
Muscle Growth ◽  
Oxidase Inhibitor ◽  
Mesenteric Arteries ◽  
Negative Regulator ◽  
Cardiometabolic Health ◽  
Obese Mice ◽  
The Metabolic Syndrome ◽  
Improve Glucose Tolerance

Increases in muscle mass, as observed with exercise, are positive influences of cardiometabolic health. Muscle mass is limited by myostatin and deletion of myostatin results in a hypermusclar phenotype that has been shown to improve glucose tolerance in obese mice. The effects on vascular and hepatic endpoints are unknown. Hypothesis: Increasing muscle mass by deletion of muscle growth negative regulator myostatin, improves NOX-limited vasodilation and hepatic steatosis. Myostatin deletion increased muscle mass in both lean (gastrocnemius 57.93%) and obese mice (gastrocnemius 79.64%). Fasting glucose, HbA1c and glucose tolerance are improved in obese myostatin null mice. Obese mice demonstrated increased markers of oxidant load and superoxide-mediated impairment of acetylcholine (Ach)-induced vasodilation compared to lean mice. Deletion of myostatin in obese mice improved Ach-induced vasodilation in mesenteric arteries without effects in lean mice. Response to nitroprusside were similar in all groups. Treatment with GKT(1х10-6 mol/L, NADPH oxidase inhibitor) restored impaired vasodilation in obese mice. Obese mice, with or without myostatin, displayed gross histological steatosis. Elevations in AST and ALT were evident in obesity and unaffected by myostatin deletion. In contrast, evidence of fibrosis (Gomori trichome, collagen mRNA expression) was reversed in obese, hypermuscular mice. Bilary dysfunction, as evidenced by increased in bilirubin, was improve in obese mice lacking myostatin as were plasma level of alkaline phosphatase. Taken together, these data suggest that increasing muscle mass by deletion of myostatin improves the metabolic syndrome as evidence by alleviation of glucose intolerance, endothelial dysfunction and hepatic fibrosis.

scholarly journals Relation between extent of myostatin depletion and muscle growth in mature mice

2009 ◽  
Vol 297 (4) ◽  
pp. E935-E940 ◽  
Author(s):  
Stephen Welle ◽  
Kerri Burgess ◽  
Charles A. Thornton ◽  
Rabi Tawil
Keyword(s):  
Muscle Mass ◽  
Normal Level ◽  
Muscle Growth ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Adult Mice ◽  
Fiber Size ◽  
Myonuclear Domain ◽  
Potential Strategy ◽  
Mapk Signaling Pathways

Myostatin is a negative regulator of muscle growth and fiber size. Changes in myostatin expression might contribute to changes in muscle mass associated with various conditions, and reducing the amount of active myostatin is a potential strategy for preventing or reversing muscle atrophy. The present study was done to determine the extent to which myostatin levels must decline to induce growth of mature muscles. Myostatin expression was reduced by activating Cre recombinase in adult mice with floxed myostatin genes. The duration of Cre activation varied from 1 to 6 wk, and the residual myostatin mRNA expression after Cre activation varied from 3 to 63% of the normal level. Promyostatin levels declined in parallel with myostatin mRNA. There was no increase in muscle mass over the 3 mo following Cre activation if residual myostatin expression was ≥40% of normal. In mice with <40% of normal myostatin expression, muscle mass increased in proportion to the extent of myostatin depletion. In mice with ≤10% of normal myostatin expression, muscle mass increased ∼25%. Myostatin depletion increased myonuclear domain volumes and the ratio of RNA to myonuclei probably by enhancing DNA transcription rather than by inhibiting RNA decay. There was no evidence that maintenance of the hypertrophy during chronic myostatin deficiency requires altered activity of Akt/mTOR or p38 MAPK signaling pathways. These data suggest that anabolic therapies based on reducing the concentration of active myostatin will be effective only if a very large proportion of the myostatin is removed or inactivated.

scholarly journals A Systematic Review with Meta-Analysis of the Effect of Resistance Training on Whole-Body Muscle Growth in Healthy Adult Males

2020 ◽  
Vol 17 (4) ◽  
pp. 1285 ◽  
Author(s):  
Pedro J. Benito ◽  
Rocío Cupeiro ◽  
Domingo J. Ramos-Campo ◽  
Pedro E. Alcaraz ◽  
Jacobo Á. Rubio-Arias
Keyword(s):  
Systematic Review ◽  
Resistance Training ◽  
Muscle Mass ◽  
Meta Analysis ◽  
Muscle Growth ◽  
Fat Free Mass ◽  
Muscle Size ◽  
Whole Body ◽  
Cochrane Library ◽  
Significant Variable

We performed a systematic review and meta-analysis to study all published clinical trial interventions, determined the magnitude of whole-body hypertrophy in humans (healthy males) and observed the individual responsibility of each variable in muscle growth after resistance training (RT). Searches were conducted in PubMed, Web of Science and the Cochrane Library from database inception until 10 May 2018 for original articles assessing the effects of RT on muscle size after interventions of more than 2 weeks of duration. Specifically, we obtain the variables fat-free mass (FMM), lean muscle mass (LMM) and skeletal muscle mass (SMM). The effects on outcomes were expressed as mean differences (MD) and a random-effects meta-analysis and meta-regressions determined covariates (age, weight, height, durations in weeks…) to explore the moderate effect related to the participants and characteristics of training. One hundred and eleven studies (158 groups, 1927 participants) reported on the effects of RT for muscle mass. RT significantly increased muscle mass (FFM+LMM+SMM; Δ1.53 kg; 95% CI [1.30, 1.76], p < 0.001; I2 = 0%, p = 1.00). Considering the overall effects of the meta-regression, and taking into account the participants’ characteristics, none of the studied covariates explained any effect on changes in muscle mass. Regarding the training characteristics, the only significant variable that explained the variance of the hypertrophy was the sets per workout, showing a significant negative interaction (MD; estimate: 1.85, 95% CI [1.45, 2.25], p < 0.001; moderator: -0.03 95% CI [−0.05, −0.001] p = 0.04). In conclusion, RT has a significant effect on the improvement of hypertrophy (~1.5 kg). The excessive sets per workout affects negatively the muscle mass gain.

Pharmacological Inhibition of Myostatin and Changes in Lean Body Mass and Lower Extremity Muscle Size in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

2014 ◽  
Vol 99 (10) ◽  
pp. E1967-E1975 ◽  
Author(s):  
Desmond Padhi ◽  
Celestia S. Higano ◽  
Neal D. Shore ◽  
Paul Sieber ◽  
Erik Rasmussen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lean Body Mass ◽  
Body Mass ◽  
Phase 1 ◽  
Muscle Growth ◽  
Androgen Deprivation ◽  
Negative Regulator ◽  
Muscle Size ◽  
Muscle Loss ◽  
Lower Extremity Muscle

Abstract Context: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat, and currently available therapies have limited efficacy to treat this complication. The antimyostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice. Objective: The objective of the study was to evaluate the safety, pharmacokinetics, and muscle efficacy of AMG 745 in men undergoing ADT for nonmetastatic prostate cancer. Methods: This was a randomized, blinded, placebo-controlled, multiple-dose, phase 1 study of AMG 745 given for 28 days. The end point of percentage change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry was prespecified. Results: Rates of adverse events (AMG 745 vs placebo) were the following: diarrhea (13% vs 9%), fatigue (13% vs 4%), contusion (10% vs 0%), and injection site bruising (6% vs 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg vs the placebo groups on day 29 by 2.2% (±0.8% SE, P = 0.008); in exploratory fat mass analysis, a decrease of −2.5% (±1.0% SE, P = 0.021) was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after day 29. Conclusion: Four weekly sc doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for nonmetastatic prostate cancer. Results support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.

scholarly journals Muscle Hyperplasia in Japanese Quail by Single Amino Acid Deletion in MSTN Propeptide

2020 ◽  
Vol 21 (4) ◽  
pp. 1504 ◽  
Author(s):  
Joonbum Lee ◽  
Dong-Hwan Kim ◽  
Kichoon Lee
Keyword(s):  
Muscle Mass ◽  
Gene Knockout ◽  
Muscle Growth ◽  
Avian Species ◽  
Negative Regulator ◽  
Single Amino Acid ◽  
Heart Weight ◽  
Dependent Manner ◽  
Base Pair Deletion ◽  
Muscle Hyperplasia

Mutation in myostatin (MSTN), a negative regulator of muscle growth in skeletal muscle, resulted in increased muscle mass in mammals and fishes. However, MSTN mutation in avian species has not been reported. The objective of this study was to generate MSTN mutation in quail and investigate the effect of MSTN mutation in avian muscle growth. Recently, a new targeted gene knockout approach for the avian species has been developed using an adenoviral CRISPR/Cas9 system. By injecting the recombinant adenovirus containing CRISPR/Cas9 into the quail blastoderm, potential germline chimeras were generated and offspring with three base-pair deletion in the targeted region of the MSTN gene was identified. This non-frameshift mutation in MSTN resulted in deletion of cysteine 42 in the MSTN propeptide region and homozygous mutant quail showed significantly increased body weight and muscle mass with muscle hyperplasia compared to heterozygous mutant and wild-type quail. In addition, decreased fat pad weight and increased heart weight were observed in MSTN mutant quail in an age- and sex-dependent manner, respectively. Taken together, these data indicate anti-myogenic function of MSTN in the avian species and the importance of cysteine 42 in regulating MSTN function.

scholarly journals Altered Neuronal Nitric Oxide Synthase in the Aging Vascular System: Implications for Estrogens Therapy

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3940-3948 ◽  
Author(s):  
Olga Lekontseva ◽  
Yanyan Jiang ◽  
Caitlyn Schleppe ◽  
Sandra T Davidge
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Vascular Function ◽  
Neuronal Nitric Oxide Synthase ◽  
Mesenteric Arteries ◽  
Superoxide Production ◽  
Therapeutic Effects ◽  
Vascular Relaxation ◽  
Enzymatic Function ◽  
Oxide Synthase

Ovarian dysfunction at any age is associated with increased cardiovascular risk in women; however, therapeutic effects of exogenous estrogens are age dependent. Estradiol (E2) activates neuronal nitric oxide synthase (nNOS) in vascular cells. Because nNOS is prone to uncoupling under unfavorable biochemical conditions (as seen in aging), E2 stimulation of nNOS may lack vascular benefits in aging. Small mesenteric arteries were isolated from female Sprague Dawley rats, 3 or 12 months old, who were ovariectomized (Ovx) and treated with placebo or E2 for 4 wk. Vascular relaxation to exogenous E2 (0.001–100 μmol/liter) ± selective nNOS inhibitor (N-propyl-l-arginine, 2 μmol/liter) or pan-NOS inhibitor [Nω-nitro-l-arginine methyl ester (l-NAME), 100 μmol/liter] was examined on wire myograph. NOS expression was measured by Western blotting in thoracic aortas, in which superoxide generation was detected as dihydroethidium (DHE) fluorescence. E2 relaxations were impaired in Ovx conditions. E2 treatment (4 wk) normalized vascular function in young rats only. Both l-N-propyl-l-arginine and l-NAME blunted E2 relaxation in young controls, but only l-NAME did so in aging controls. NOS inhibition had no effect on acute E2 relaxation in Ovx rats, regardless of age or treatment. nNOS expression was similar in all animal groups. However, nNOS inhibition increased DHE fluorescence in young controls, whereas it reduced it in aging or Ovx animals. In E2-treated animals of either age, superoxide production was NOS independent. In conclusion, nNOS contributed to vascular relaxation in young, but not aging rats, where its enzymatic function shifted toward superoxide production. Thus, nNOS dysfunction may explain a mechanism of impaired E2 signaling in aging conditions.

scholarly journals The Orphan Nuclear Receptor Nur77 Is a Determinant of Myofiber Size and Muscle Mass in Mice

2015 ◽  
Vol 35 (7) ◽  
pp. 1125-1138 ◽  
Author(s):  
Peter Tontonoz ◽  
Omar Cortez-Toledo ◽  
Kevin Wroblewski ◽  
Cynthia Hong ◽  
Laura Lim ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Nuclear Receptor ◽  
Muscle Growth ◽  
Muscle Size ◽  
Orphan Nuclear Receptor ◽  
Loss Of Function ◽  
Transgenic Expression ◽  
Primary Myoblasts ◽  
A Cell

We previously showed that the orphan nuclear receptor Nur77 (Nr4a1) plays an important role in the regulation of glucose homeostasis and oxidative metabolism in skeletal muscle. Here, we show using both gain- and loss-of-function models that Nur77 is also a regulator of muscle growth in mice. Transgenic expression of Nur77 in skeletal muscle in mice led to increases in myofiber size. Conversely, mice with global or muscle-specific deficiency in Nur77 exhibited reduced muscle mass and myofiber size. In contrast to Nur77 deficiency, deletion of the highly related nuclear receptor NOR1 (Nr4a3) had minimal effect on muscle mass and myofiber size. We further show that Nur77 mediates its effects on muscle size by orchestrating transcriptional programs that favor muscle growth, including the induction of insulin-like growth factor 1 (IGF1), as well as concomitant downregulation of growth-inhibitory genes, including myostatin, Fbxo32 (MAFbx), and Trim63 (MuRF1). Nur77-mediated increase in IGF1 led to activation of the Akt-mTOR-S6K cascade and the inhibition of FoxO3a activity. The dependence of Nur77 on IGF1 was recapitulated in primary myoblasts, establishing this as a cell-autonomous effect. Collectively, our findings identify Nur77 as a novel regulator of myofiber size and a potential transcriptional link between cellular metabolism and muscle growth.

scholarly journals Obesity Induces Artery-Specific Alterations: Evaluation of Vascular Function and Inflammatory and Smooth Muscle Phenotypic Markers

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Antonio Garcia Soares ◽  
Maria Helena Catelli de Carvalho ◽  
Eliana Akamine
Keyword(s):  
Smooth Muscle ◽  
Mrna Expression ◽  
Vascular Function ◽  
Vascular Reactivity ◽  
Mesenteric Arteries ◽  
Collagen Deposition ◽  
Obese Mice ◽  
Phenotypic Markers ◽  
Expression Of Genes ◽  
The Impact

Vascular alterations are expected to occur in obese individuals but the impact of obesity could be different depending on the artery type. We aimed to evaluate the obesity effects on the relaxing and contractile responses and inflammatory and smooth muscle (SM) phenotypic markers in two vascular beds. Obesity was induced in C57Bl/6 mice by 16-week high-fat diet and vascular reactivity, mRNA expression of inflammatory and SM phenotypic markers, and collagen deposition were evaluated in small mesenteric arteries (SMA) and thoracic aorta (TA). Endothelium-dependent relaxation in SMA and TA was not modified by obesity. In contrast, contraction induced by depolarization and contractile agonists was reduced in SMA, whereas only contraction induced by adrenergic agonist was reduced in TA of obese mice. Obesity increased the mRNA expression of pro- and anti-inflammatory cytokines in SMA and TA. The expression of genes necessary for maintaining contractile ability was increased by obesity, but the increase was more pronounced in TA. Collagen deposition was increased in SMA, but not in TA, of obese mice. Although the endothelial function was still preserved, the SM of the two artery types was impaired by obesity, but the impairment was higher in SMA, which could be associated with SM phenotypic changes.

Fetal origins of adult vascular dysfunction in mice lacking endothelial nitric oxide synthase

2005 ◽  
Vol 288 (5) ◽  
pp. R1114-R1121 ◽  
Author(s):  
Monica Longo ◽  
Venu Jain ◽  
Yuri P. Vedernikov ◽  
Radek Bukowski ◽  
Robert E. Garfield ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Mesenteric Arteries ◽  
Fetal Origins ◽  
Uterine Environment ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Epidemiological studies have shown increased incidence of hypertension and coronary artery disease in growth-restricted fetuses during their adult life. A novel animal model was used to test the hypothesis regarding the role of an abnormal uterine environment in fetal programming of adult vascular dysfunction. Mice lacking a functional endothelial nitric oxide synthase (NOS3−/−KO, where KO is knockout) and wild-type (WT) mice (NOS3+/+WT) were crossbred to produce homozygous NOS3−/−KO, maternally derived heterozygous (NOS3+/−mat, mother with NOS3 deficiency), paternally derived heterozygous (NOS3+/−pat, normal mother), and NOS3+/+WT litters. Number of fetuses per litter was smaller in NOS3−/−KO and NOS3+/−mat compared with NOS3+/−pat and NOS3+/+WT mice. Adult female mice from these litters (7–8 wk old) were killed, and ring preparations of carotid and mesenteric arteries were mounted in a wire myograph to evaluate the passive and reactive vascular characteristics. Slope of the length-tension plot (a measure of vascular compliance) was increased, and optimal diameter (as calculated by Laplace equation) was decreased in NOS3−/−KO and NOS3+/−mat compared with NOS3+/−pat and NOS3+/+WT mice. Acetylcholine caused vasorelaxation in NOS3+/−pat and NOS3+/+WT and contraction in NOS3−/−KO and NOS3+/−mat mice. Responses to phenylephrine and Ca2+ were increased in NOS3−/−KO and NOS3+/−mat compared with NOS3+/−pat and NOS3+/+WT mice. Relaxation to isoproterenol was decreased in NOS3−/−KO and NOS3+/−mat vs. NOS3+/−pat and NOS3+/+WT mice. Abnormalities in the passive and reactive in vitro vascular properties seen in NOS+/−mat that developed in a NOS3-deficient maternal/uterine environment compared with the genetically identical NOS3+/−pat mice that developed in a normal environment are the first direct evidence in support of a role for uterine environment in determining vascular function in later life.

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