TRPV4 deficiency increases skeletal muscle metabolic capacity and resistance against diet-induced obesity

2012 ◽  
Vol 112 (7) ◽  
pp. 1223-1232 ◽  
Author(s):  
Tatsuya Kusudo ◽  
Zhonghua Wang ◽  
Atsuko Mizuno ◽  
Makoto Suzuki ◽  
Hitoshi Yamashita
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Transient Receptor Potential ◽  
Thermal Sensation ◽  
Chow Diet ◽  
Type I ◽  
Wild Type ◽  
Diet Induced Obesity ◽  
Obesity In Mice

Transient receptor potential channel V4 (TRPV4) functions as a nonselective cation channel in various cells and plays physiological roles in osmotic and thermal sensation. However, the function of TRPV4 in energy metabolism is unknown. Here, we report that TRPV4 deficiency results in increased muscle oxidative capacity and resistance to diet-induced obesity in mice. Although no difference in body weight was observed between wild-type and Trpv4−/− mice when fed a standard chow diet, obesity phenotypes induced by a high-fat diet were significantly improved in Trpv4−/− mice, without any change in food intake. Quantitative analysis of mRNA revealed the constitutive upregulation of many genes, including those for transcription factors such as peroxisome proliferator-activated receptor α and for metabolic enzymes such as phosphoenolpyruvate carboxykinase. These upregulated genes were especially prominent in oxidative skeletal muscle, in which the activity of Ca2+-dependent phosphatase calcineurin was elevated, suggesting that other Ca2+ channels function in the skeletal muscle of Trpv4−/− mice. Indeed, gene expressions for TRPC3 and TRPC6 increased in the muscles of Trpv4−/− mice compared with those of wild-type mice. The number of oxidative type I fiber also increased in the mutant muscles following myogenin gene induction. These results strongly suggested that inactivation of Trpv4 induces compensatory increases in TRPC3 and TRPC6 production, and elevation of calcineurin activity, affecting energy metabolism through increased expression of genes involved in fuel oxidation in skeletal muscle and thereby contributing to increased energy expenditure and protection from diet-induced obesity in mice.

Implication of the satellite cell in dystrophic muscle fibrosis: a self-perpetuating mechanism of collagen overproduction

2007 ◽  
Vol 293 (2) ◽  
pp. C661-C669 ◽  
Author(s):  
Catherine Alexakis ◽  
Terence Partridge ◽  
George Bou-Gharios
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Collagen Type ◽  
Collagen Type I ◽  
C2c12 Cells ◽  
Type I ◽  
Wild Type ◽  
Dystrophic Muscle ◽  
Type Iii

Because of its mechanical function, skeletal muscle is heavily influenced by the composition of its extracellular matrix (ECM). Fibrosis generated by chronic damage, such as occurs in muscular dystrophies, is thus particularly disastrous in this tissue. Here, we examined the interrelationship between the muscle satellite cell and the production of collagen type I, a major component of fibrotic ECM, by using both C2C12, a satellite cell-derived cell line, and primary muscle satellite cells. In C2C12 cells, we found that expression of collagen type I mRNA decreases substantially during skeletal muscle differentiation. On a single-cell level, collagen type I and myogenin became mutually exclusive after 3 days in differentiation medium, whereas addition of collagen markedly suppressed differentiation of C2C12 cells. Primary cultures of satellite cells associated with isolated single fibers of the young (4 wk old) mdx dystrophic mouse and of C57BL/10ScSn wild-type controls expressed collagen type I and type III mRNA and protein. This pattern persisted in wild-type mice at all ages. But, curiously, in older (18-mo-old) mdx mice, although the myogenic cells continued to express type III collagen, type I expression became restricted to nonmyogenic cells. These cells typically constituted part of a cellular sheet surrounding the old mdx fibers. This combination of features strongly suggests that the progression to fibrosis in dystrophic muscle involves changes in the mechanisms controlling matrix production, which generates positive feedback that results in a reprogramming of myoblasts to a profibrotic function.

scholarly journals Nicotinamide Nucleotide Transhydrogenase (Nnt) is Related to Obesity in Mice

2020 ◽  
Vol 52 (12) ◽  
pp. 877-881
Author(s):  
Anne Kunath ◽  
John T. Heiker ◽  
Matthias Kern ◽  
Joanna Kosacka ◽  
Gesine Flehmig ◽  
...  
Keyword(s):  
Fat Mass ◽  
Metabolic Diseases ◽  
Body Weight Gain ◽  
Wild Type ◽  
Inner Mitochondrial Membrane ◽  
Nicotinamide Nucleotide Transhydrogenase ◽  
Diet Induced Obesity ◽  
Highly Sensitive ◽  
Obesity In Mice

AbstractThe C57BL/6J (B6J) mouse strain has been widely used as a control strain for the study of metabolic diseases and diet induced obesity (DIO). B6J mice carry a spontaneous deletion mutation in the nicotinamide nucleotide transhydrogenase (Nnt) gene eliminating exons 7–11, resulting in expression of a truncated form of Nnt, an enzyme that pumps protons across the inner mitochondrial membrane. It has been proposed that this mutation in B6J mice is associated with epigonadal fat mass and altered sensitivity to diet induced obesity. To define the role of Nnt in the development of diet induced obesity, we generated first backcross (BC1) hybrids of wild type Nnt C57BL/6NTac and mutated Nnt C57BL/6JRj [(C57BL/6NTac×C57BL/6JRj)F1×C57BL/6NTac]. Body weight gain and specific fat-pad depot mass were measured in BC1 hybrids under high fat diet conditions. Both sexes of BC1 hybrids indicate that mice with Nnt wild type allele are highly sensitive to DIO and exhibit higher relative fat mass. In summary, our data indicate that the Nnt mutation in mice is associated with sensitivity to DIO and fat mass.

scholarly journals CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice

2019 ◽  
Vol 317 (6) ◽  
pp. E973-E983 ◽  
Author(s):  
Annie Hasib ◽  
Chandani K. Hennayake ◽  
Deanna P. Bracy ◽  
Aimée R. Bugler-Lamb ◽  
Louise Lantier ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
High Fat Diet ◽  
Critical Role ◽  
Chow Diet ◽  
Wild Type ◽  
High Fat ◽  
Insulin Resistant ◽  
Beneficial Effects

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient ( cd44−/−) mice and wild-type littermates ( cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44−/− mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44−/− mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44−/− mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44−/− compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44−/− mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44−/− mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

scholarly journals SIM1 Overexpression Partially Rescues Agouti Yellow and Diet-Induced Obesity by Normalizing Food Intake

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4542-4549 ◽  
Author(s):  
Bassil M. Kublaoui ◽  
J. Lloyd Holder ◽  
Kristen P. Tolson ◽  
Terry Gemelli ◽  
Andrew R. Zinn
Keyword(s):  
Food Intake ◽  
Energy Expenditure ◽  
Transgenic Mice ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Enhanced Sensitivity ◽  
Diet Induced Obesity ◽  
Melanocortin 4 Receptor ◽  
Obesity In Mice

Single-minded 1 (SIM1) mutations are associated with obesity in mice and humans. Haploinsufficiency of mouse Sim1 causes hyperphagic obesity with increased linear growth and enhanced sensitivity to a high-fat diet, a phenotype similar to that of agouti yellow and melanocortin 4 receptor knockout mice. To investigate the effects of increased Sim1 dosage, we generated transgenic mice that overexpress human SIM1 and examined their phenotype. Compared with wild-type mice, SIM1 transgenic mice had no obvious phenotype on a low-fat chow diet but were resistant to diet-induced obesity on a high-fat diet due to reduced food intake with no change in energy expenditure. The SIM1 transgene also completely rescued the hyperphagia and partially rescued the obesity of agouti yellow mice, in which melanocortin signaling is abrogated. Our results indicate that the melanocortin 4 receptor signals through Sim1 or its transcriptional targets in controlling food intake but not energy expenditure.

scholarly journals Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity

2012 ◽  
Vol 302 (12) ◽  
pp. E1502-E1510 ◽  
Author(s):  
Jin Kwon Jeong ◽  
Gyorgyi Szabo ◽  
Giuseppina Mattace Raso ◽  
Rosaria Meli ◽  
Sabrina Diano
Keyword(s):  
Liver Weight ◽  
Metabolic Parameters ◽  
Metabolic Effects ◽  
Chow Diet ◽  
Mrna Levels ◽  
Wild Type ◽  
Glucose Levels ◽  
Melanocyte Stimulating Hormone ◽  
Diet Induced Obesity ◽  
Standard Chow Diet

α-Melanocyte-stimulating hormone (α-MSH) is a critical regulator of energy metabolism. Prolyl carboxypeptidase (PRCP) is an enzyme responsible for its degradation and inactivation. PRCP-null mice ( PRCP gt/gt) showed elevated levels of brain α-MSH, reduced food intake, and a leaner phenotype compared with wild-type controls. In addition, they were protected against diet-induced obesity. Here, we show that PRCP gt/gt animals have improved metabolic parameters compared with wild-type controls under a standard chow diet (SD) as well as on a high-fat diet (HFD). Similarly to when they are exposed to SD, PRCP gt/gt mice exposed to HFD for 13 wk showed a leaner phenotype due to decreased fat mass, increased energy expenditure, and locomotor activity. They also showed improved insulin sensitivity and glucose tolerance compared with WT controls and a significant reduction in fasting glucose levels. These improvements occured before changes in body weight and composition were evident, suggesting that the beneficial effect of PRCP ablation is independent of the adiposity levels. In support of a reduced gluconeogenesis, liver PEPCK and G-6-Pase mRNA levels were reduced significantly in PRCPgt/gt compared with WT mice. A significant decrease in liver weight and hepatic triglycerides were also observed in PRCP gt/gt compared with WT mice. Altogether, our data suggest that PRCP is an important regulator of energy and glucose homeostasis since its deletion significantly improves metabolic parameters in mice exposed to both SD and HFD.

scholarly journals OR-035 Effect of Aerobic Training on the Exercise Capacity of Apelin Knock-out Mice

2018 ◽  
Vol 1 (2) ◽  
Author(s):  
Lu Yan ◽  
Tieying Li ◽  
Ying Zhang
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Oxygen Uptake ◽  
Exercise Capacity ◽  
Aerobic Training ◽  
Movement Time ◽  
Wild Type ◽  
Running Speed ◽  
Knock Out ◽  
Knock Out Mice

Objective Aerobic training is considered to be an effective way to enhance the body’s exercise capacity which is closely related to the improvement of skeletal muscle energy metabolism. And as a new myokine, apelin has been found to play a key role in regulating the energy metabolism of skeletal muscle. However, whether the loss of apelin gene affects exercise capacity and what role aerobic training play in it remains unknown. This study was designed to investigate the effect of apelin on exercise capacity during aerobic training and to provide a theoretical basis for the mechanism of aerobic exercise affecting exercise capacity. Methods Male C57BL/6J wild type mouse(n=20) and apelin knock-out mouse(n=20) were assigned by random allocation to four groups(n=10): wild type control(WC), wild type exercised(WE), apelin knock-out control(KC) and apelin knock-out exercised(KE). Exercise training consisted of treadmill running 60 minutes/day ×6 days/week for 4 weeks. The training intensity corresponded to the 70-75% maximum oxygen uptake of mice. The running speed was 15m/min with an incline of +5° in the first 2 weeks and subsequently adjusted to 20m/min according to the maximum oxygen uptake in the last 2 weeks. On the day after training, all groups were forced to perform a incremental exercise test to exhaustion. This test was started with an incline of +5°and a speed of 10 m/min for 5 min. After this initial phase, the speed was progressively increased by 3m/min every 3 min until animal exhausted. The maximum running speed, movement time and distance were recorded during the test. Results Compared with group WC, the maximum running speed, movement time and distance of group KC were significantly decreased(P<0.01). And the maximum running speed, movement time and distance of group KE were clearly higher than those of group KC(P<0.01). There is no significant difference between group WE and group WC, and between group KE and group WE. Conclusions The exercise capacity of mice was significantly decreased because of knocking out the apelin gene, and the exercise ability of apelin knock-out mice can be clearly enhanced by aerobic training.

scholarly journals Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse

2007 ◽  
Vol 282 (45) ◽  
pp. 32844-32855 ◽  
Author(s):  
Parvin Hakimi ◽  
Jianqi Yang ◽  
Gemma Casadesus ◽  
Duna Massillon ◽  
Fatima Tolentino-Silva ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Phosphoenolpyruvate Carboxykinase

scholarly journals Enoxacin induces oxidative metabolism and mitigates obesity by regulating adipose tissue miRNA expression

2020 ◽  
Vol 6 (49) ◽  
pp. eabc6250
Author(s):  
Andréa Livia Rocha ◽  
Tanes Imamura de Lima ◽  
Gerson Profeta de Souza ◽  
Renan Oliveira Corrêa ◽  
Danilo Lopes Ferrucci ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Mirna Expression ◽  
Oxidative Metabolism ◽  
Target Genes ◽  
Cell Models ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Obesity In Mice

MicroRNAs (miRNAs) have been implicated in oxidative metabolism and brown/beige adipocyte identity. Here, we tested whether widespread changes in miRNA expression promoted by treatment with the small-molecule enoxacin cause browning and prevent obesity. Enoxacin mitigated diet-induced obesity in mice, and this was associated with increased energy expenditure. Consistently, subcutaneous white and brown adipose tissues and skeletal muscle of enoxacin-treated mice had higher levels of markers associated with thermogenesis and oxidative metabolism. These effects were cell autonomous since they were recapitulated in vitro in murine and human cell models. In preadipocytes, enoxacin led to a reduction of miR-34a-5p expression and up-regulation of its target genes (e.g., Fgfr1, Klb, and Sirt1), thus increasing FGF21 signaling and promoting beige adipogenesis. Our data demonstrate that enoxacin counteracts obesity by promoting thermogenic signaling and inducing oxidative metabolism in adipose tissue and skeletal muscle in a mechanism that involves, at least in part, miRNA-mediated regulation.

scholarly journals The Effects of Diet Induced Obesity (DIO) on Skeletal Muscle Transcription in MuRF1 KO Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A59-A59
Author(s):  
Andrea Gail Marshall ◽  
Jennifer E Norman ◽  
Michael S Chementi ◽  
John C Rutledge ◽  
Sue C Bodine
Keyword(s):  
Skeletal Muscle ◽  
Type Ii Diabetes ◽  
Gastrocnemius Muscle ◽  
Transcriptional Response ◽  
Chow Diet ◽  
Male And Female ◽  
Diet Induced Obesity ◽  
Males And Females ◽  
The Impact ◽  
Skeletal Muscle Transcriptome

Abstract Background: As obesity and Type II Diabetes rise globally, it is important to understand the similarities and differences in the response of metabolic tissues between males and females. We wanted to evaluate the impact of prolonged diet induced obesity (DIO) on the skeletal muscle transcriptome of our MuRF1 KO (KO) mice. Methods: RNA was isolated from the gastrocnemius muscle of male and female WT and KO mice that were fed either standard chow (Envigo 2918) or a 45% HFD (Research Diets D12451) for 22 weeks (n = 4). RNA was enriched for mRNA prior to library preparation. RNA sequencing was performed using 150 bp paired-end reads (~ 31.6 M reads per sample). Differentially expressed genes (DEGs) were identified using DESeq2 with an FDR set to 5%. Results: At baseline (chow diet), both male and female KO mice had DEGs compared to their WT counterparts (male, 1174; female, 105). Most DEGs were found to be unique by sex (male, 1151; female, 82), though 23 genes were found to be changed in common. After obesity was induced by 22 weeks of 45% HFD feeding, KO animals showed a greater transcriptional response than their WT counterparts. Males had 1821 DEGs (v. 179 in WT) while females had 4425 DEGs (v. 2090 in WT). In males, 78 genes were changed in common between WT and KO in response to DIO, with 76 of those genes changing in the same direction (Slc282a and Gm15427 did not). In females, 1445 genes were changed in common between WT and KO, with all but 2 genes (Pla2g7 and Zfp385b) changing in the same direction. In both male and female KO animals, oxidative phosphorylation and ribosomal pathways were most significant, though the direction of change in the DEGs was opposite. Conclusion: In skeletal muscle, sex highly influences the genes and pathways changed in response to DIO. Even among common pathways identified, the response between males and females differed. Loss of MuRF1 results in common and unique transcript changes in and between males and females under normal conditions and in DIO.

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