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Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

ABSTRACT: 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.

SUBMITTER: Gonzalez-Mariscal I

PROVIDER: S-EPMC6988864 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

González-Mariscal Isabel I Montoro Rodrigo A RA O'Connell Jennifer F JF Kim Yoo Y Gonzalez-Freire Marta M Liu Qing-Rong QR Alfaras Irene I Carlson Olga D OD Lehrmann Elin E Zhang Yongqing Y Becker Kevin G KG Hardivillé Stéphan S Ghosh Paritosh P Egan Josephine M JM

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20190206 5

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 pancrea ...[more]

PMID: 30726112

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Project description:Volumetric muscle loss (VML) is the traumatic loss of skeletal muscle, resulting in chronic functional deficits and pathological comorbidities, including altered whole-body metabolic rate and respiratory exchange ratio (RER), despite no change in physical activity in animal models. In other injury models, treatment with β2 receptor agonists (e.g. formoterol) improves metabolic and skeletal muscle function. We aimed first to examine if restricting physical activity following injury affects metabolic and skeletal muscle function, and second, to enhance the metabolic and contractile function of the muscle remaining following VML injury through treatment with formoterol. Adult male C57Bl/6J mice (n = 32) underwent VML injury to the posterior hindlimb compartment and were randomly assigned to unrestricted or restricted activity and formoterol treatment or no treatment; age-matched injury naïve mice (n = 4) were controls for biochemical analyses. Longitudinal 24 h evaluations of physical activity and whole-body metabolism were conducted following VML. In vivo muscle function was assessed terminally, and muscles were biochemically evaluated for protein expression, mitochondrial enzyme activity and untargeted metabolomics. Restricting activity chronically after VML had the greatest effect on physical activity and RER, reflected in reduced lipid oxidation, although changes were attenuated by formoterol treatment. Formoterol enhanced injured muscle mass, while mitigating functional deficits. These novel findings indicate physical activity restriction may recapitulate following VML clinically, and adjunctive oxidative treatment may create a metabolically beneficial intramuscular environment while enhancing the injured muscle's mass and force-producing capacity. Further investigation is needed to evaluate adjunctive oxidative treatment with rehabilitation, which may augment the muscle's regenerative and functional capacity following VML. KEY POINTS: The natural ability of skeletal muscle to regenerate and recover function is lost following complex traumatic musculoskeletal injury, such as volumetric muscle loss (VML), and physical inactivity following VML may incur additional deleterious consequences for muscle and metabolic health. Modelling VML injury-induced physical activity restriction altered whole-body metabolism, primarily by decreasing lipid oxidation, while preserving local skeletal muscle metabolic activity. The β2 adrenergic receptor agonist formoterol has shown promise in other severe injury models to improve regeneration, recover function and enhance metabolism. Treatment with formoterol enhanced mass of the injured muscle and whole-body metabolism while mitigating functional deficits resulting from injury. Understanding of chronic effects of the clinically available and FDA-approved pharmaceutical formoterol could be a translational option to support muscle function after VML injury.

Project description:Abstract Background: Friedreich’s Ataxia (FA) is a neurodegenerative disease caused by disruptions in the gene encoding frataxin, a protein involved in formation of the iron-sulfur clusters needed for mitochondrial oxidative phosphorylation (OXPHOS). FA confers an increased risk for diabetes mellitus, but the mechanisms underlying this propensity are not well understood. Design: Cross-sectional study (clinicaltrials.gov: NCT02920671) Methods: Participants were non-diabetic individuals with FA (ages 18y-<65y) and healthy controls with a similar distribution of age, sex, BMI, and ancestry. OXPHOS capacity of calf muscle was assessed using a non-invasive, exercise-based MRI technique, creatine chemical exchange saturation transfer (CrCEST); results for lateral gastrocnemius (LG), the most consistently exercised muscle, are shown. After an overnight fast, a stable isotope tracer-enhanced oral glucose tolerance test was done. Body composition was assessed using dual energy x-ray absorptiometry. Linear regression analyses of the entire sample tested the association between outcomes and covariates (results are shown as standardized coefficient β). Results: This interim analysis has n=34 participants (11 FA, 23 control). Participants with FA were 61% male, median age 27y (IQI, 23-39), median BMI 26.9 kg/m2 (IQI, 24.1-29.4), and median visceral fat mass 0.50 kg (IQI, 0.35-0.70). Controls were 61% male, median age 29y (IQI, 26-38), median BMI 24.6 kg/m2 (IQI, 21.7-28.5), and median visceral fat mass 0.45 kg (IQI, 0.27-0.64). Fasting glucose was higher in FA (91 vs. 82 mg/dL, p=0.006). Lactate was similar at baseline and increased after oral glucose in both, but remained higher after 180min in FA (at 210min, 1.13 vs. 0.88 mmol/L, p=0.01). Post-exercise CrCEST recovery time constant (τCr) was increased 2.2-fold in FA (p=0.02), consistent with decreased OXPHOS capacity. In univariate analyses, whole body insulin sensitivity (WBISI) was decreased in FA (β -1.14, p=0.003), decreased with longer τCr, (β -0.48, p=0.01), and decreased with higher visceral fat (β -0.55, p=0.004). In multivariate analyses, these associations were attenuated when FA diagnosis (β -0.85, p=0.06) and τCr (β -0.25, p=0.25) were included in the same model, but were persistent when FA diagnosis (β -0.93, p=0.008) and visceral fat (β -0.43, p=0.01) were included in the same model. In univariate analyses, lactate area under the curve (AUC) was nominally increased in FA (β 0.67, p=0.11), and significantly positively associated with longer τCr (β 0.51, p=0.008). Conclusions: Individuals with a genetic mitochondrial disorder conferring increased diabetes risk have decreased whole body insulin sensitivity that may be mediated by decreased skeletal muscle OXPHOS capacity. Studies in rare disorders may provide insights into the role of skeletal muscle metabolism in the pathogenesis of Type 2 diabetes. Funding: NIH/NIDDK Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Dataset Information

Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

Publications

Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

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