Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.
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ABSTRACT:
PROVIDER: PRJNA431858 | ENA |
REPOSITORIES: ENA
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Project description:Cannabinoid 1 receptor (CB1R) plays a critical role in the regulation of whole-body energy metabolism because of its involvement in controlling food intake thorough a central mechanism, and controlling distribution of fuel and utilization in the periphery, particularly in fat and liver. Additionally, inhibition of CB1R improves insulin secretion from pancreatic beta cells and insulin sensitivity in both pancreatic beta cells and hepatocytes. We now developed a skeletal muscle-specific CB1R-knockout (Skm-CB1R-/-) mouse to study the specific role of CB1R in muscle. Muscle-CB1R ablation prevented diet-induced and age-induced insulin resistance by increasing insulin receptor signaling. Ablation of CB1R in muscle also led to IL-6 secretion and reduced myostatin expression, and enhanced AKT and MAPKs signaling. These changes in myokines induced the expression of myogenic genes, increasing muscle mass and whole-body lean/fat ratio in both obesity and aging, with no change in total body weight. Skm-CB1R-/- mice had increased energy expenditure and their muscle had improved mitochondrial performance, which led to improved physical endurance. These results collectively show that muscle-CB1R is involved in regulating whole-body insulin sensitivity and physical performance.
2020-01-22 | GSE109741 | GEO
Project description:Sarcopenic obesity, the combination of skeletal muscle mass and function loss with an increase in body fat, is associated with physical limitations, cardiovascular diseases, metabolic stress, and increased risk of mortality. Cannabinoid receptor type 1 (CB1R) plays a critical role in the regulation of whole-body energy metabolism because of its involvement in controlling appetite, fuel distribution, and utilization. Inhibition of CB1R improves insulin secretion and insulin sensitivity in pancreatic β-cells and hepatocytes. We have now developed a skeletal muscle-specific CB1R-knockout (Skm-CB1R-/-) mouse to study the specific role of CB1R in muscle. Muscle-CB1R ablation prevented diet-induced and age-induced insulin resistance by increasing IR signaling. Moreover, muscle-CB1R ablation enhanced AKT signaling, reducing myostatin expression and increasing IL-6 secretion. Subsequently, muscle-CB1R ablation increased myogenesis through its action on MAPK-mediated myogenic gene expression. Consequently, Skm-CB1R-/- mice had increased muscle mass and whole-body lean/fat ratio in obesity and aging. Muscle-CB1R ablation improved mitochondrial performance, leading to increased whole-body muscle energy expenditure and improved physical endurance, with no change in body weight. These results collectively show that CB1R in muscle is sufficient to regulate whole-body metabolism and physical performance and is a novel target for the treatment of sarcopenic obesity. -González-Mariscal, I., Montoro, R. A., O'Connell, J. F., Kim, Y., Gonzalez-Freire, M., Liu, Q.-R., Alfaras, I., Carlson, O. D., Lehrmann, E., Zhang, Y., Becker, K. G., Hardivillé, S., Ghosh, P., Egan, J. M. Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.
| S-EPMC6988864 | biostudies-literature
Project description:The purpose of this study was to determine whether postdevelopmental myostatin depletion influenced the changes in skeletal muscle gene expression profiles induced by a long-term increase in physical activity. Myostatin levels in muscles of adult male mice with floxed myostatin genes were reduced ~85% by activating Cre recombinase. Control mice with normal myostatin genes had the same Cre-activating treatment. Some of the mice were housed in ordinary cages throughout the study, limiting their physical activity. Other mice were given free access to running wheels for the final 12 weeks of the study. At the end of the study, comprehensive gene expression profiles of triceps brachii muscles were determined by RNA sequencing (RNA-Seq), with muscles from mice selected for similarity of running behavior throughout the period of wheel access. Wheel running increased expression of hundreds of mRNAs encoding proteins involved in oxidative energy metabolism, and this response was not affected by myostatin deficiency. The running-induced increase in the ratio of Myh1 mRNA (which encodes myosin heavy chain type 2x) to Myh4 mRNA (which encodes myosin heavy chain type 2b) also was not affected by myostatin depletion. At every threshold of P (computed by analysis of variance), the number of transcripts with interactions between activity level and myostatin level was fewer than the number expected by chance. These data suggest that myostatin is not required for transcriptional adaptations to moderate-intensity exercise. 12 samples, 6 from sedentary mice and 6 from active (wheel running) mice. 3 control and 3 myostatin-deficient mice within each activity level.
2011-09-02 | E-GEOD-31839 | biostudies-arrayexpress
Project description:The purpose of this study was to determine whether postdevelopmental myostatin depletion influenced the changes in skeletal muscle gene expression profiles induced by a long-term increase in physical activity. Myostatin levels in muscles of adult male mice with floxed myostatin genes were reduced ~85% by activating Cre recombinase. Control mice with normal myostatin genes had the same Cre-activating treatment. Some of the mice were housed in ordinary cages throughout the study, limiting their physical activity. Other mice were given free access to running wheels for the final 12 weeks of the study. At the end of the study, comprehensive gene expression profiles of triceps brachii muscles were determined by RNA sequencing (RNA-Seq), with muscles from mice selected for similarity of running behavior throughout the period of wheel access. Wheel running increased expression of hundreds of mRNAs encoding proteins involved in oxidative energy metabolism, and this response was not affected by myostatin deficiency. The running-induced increase in the ratio of Myh1 mRNA (which encodes myosin heavy chain type 2x) to Myh4 mRNA (which encodes myosin heavy chain type 2b) also was not affected by myostatin depletion. At every threshold of P (computed by analysis of variance), the number of transcripts with interactions between activity level and myostatin level was fewer than the number expected by chance. These data suggest that myostatin is not required for transcriptional adaptations to moderate-intensity exercise.
2011-09-03 | GSE31839 | GEO
Project description:Inhibition of myostatin signaling induces strong skeletal muscle growth making it an attractive target to treat muscle wasting and sarcopenia. However, the biological function of myostatin in the heart is barely understood. We demonstrate that conditional inactivation of myostatin in the adult murine heart leads to cardiac hypertrophy, heart failure and increased lethality. To induce cardiomyocyte specific loss of myostatin a conditionally active Mstn^fl/fl allele was generated by insertion of loxP elements upstream and downstream of exons 1 and 2 of the mouse myostatin gene. The selection cassette was removed in vivo by flp-recombination. To inactivate myostatin, mice were mated to alphaMyHC-MCM mice (Sohal, DS, et al. (2001) Circulation Research 89, 20-25). Cre-recombination was achieved by intraperitoneal administration of Tamoxifen (40 mg/kg) for 5 consecutive days. The respective control alphaMyHC-MCM animals were equally treated.
2014-05-16 | E-MEXP-3744 | biostudies-arrayexpress
Project description:To identify microRNAs involved in myostatin-deficient muscular hypertrophy, we compared miRNA expression in wild-type and myostatin knockout mice.
2013-12-17 | GSE49523 | GEO
Project description:To identify microRNAs involved in myostatin-deficient muscular hypertrophy, we compared miRNA expression in wild-type and myostatin knockout mice. Total RNA, isolated from three wild-type or myostatin knockout mice, was pooled and then used for microarray analysis.
2013-12-17 | E-GEOD-49523 | biostudies-arrayexpress
Project description:RNA from 5 mice with postdevelopmental knockout of myostatin and 5 mice with normal myostatin expression was analyzed with comprehensive oligonucleotide microarrays. Myostatin depletion affected the expression of several hundred genes at nominal P < 0.01, but fewer than a hundred effects were statistically significant according to a more stringent criterion (false discovery rate < 5%). Most of the effects were less than 1.5-fold in magnitude. In contrast to previously-reported effects of constitutive myostatin knockout, postdevelopmental knockout did not downregulate expression of genes encoding slow isoforms of contractile proteins or genes encoding proteins involved in energy metabolism. Several collagen genes were expressed at lower levels in the myostatin-deficient muscles, and this led to reduced tissue collagen levels as reflected by hydroxyproline content. Myostatin knockout tended to down-regulate the expression of sets of genes with promoter motifs for Smad3, Smad4, myogenin, NF-κB, serum response factor, and numerous other transcription factors. Main conclusions: in mature muscle, myostatin is a key transcriptional regulator of collagen genes, but not genes encoding contractile proteins or genes encoding proteins involved in energy metabolism.
2009-03-24 | GSE15349 | GEO
Project description:We tested the effects of isopropoyl dodecyl fluorophosphonate (IDFP) (10 mg/kg, i.p.), a pharmacological inhibitor of endocannabinoid degradation, on hepatic gene expression in mice. To determine if increased cannabinoid receptor 1 signaling is responsible for IDFP induced effects a subset of mice were pretreated with the cannabinoid receptor 1 antagonist (AM251) (10 mg/kg, i.p.). Total RNA obtained from liver of mice treated with DMSO (n=6), IDFP (n=8), or AM251/IDFP (n=5) (all 10 mg/kg i.p.) for 4 hours.
2011-09-30 | E-GEOD-22949 | biostudies-arrayexpress
Project description:Because myostatin normally limits skeletal muscle growth, there is an extensive effort to develop myostatin inhibitors for clinical use. One potential concern is that in patients with muscle degenerative diseases, inducing hypertrophy may increase stress on dystrophic fibers. Here, we show that blocking the myostatin pathway in dysferlin mutant mice results in early improvement in histopathology but ultimately accelerates muscle degeneration. Hence, benefits of this approach should be weighed against these potential detrimental effects.
2015-09-04 | GSE62945 | GEO