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Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity.

Guo T, Jou W, Chanturiya T, Portas J, Gavrilova O, McPherron AC - PLoS ONE (2009)

Bottom Line: To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle.We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet.In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity.

View Article: PubMed Central - PubMed

Affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn(-/-) mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn(-/-) mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn(-/-) mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn(-/-) mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn(-/-) mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn(-/-) mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes.

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Adaptation to increased muscle mass.(A) Relative mRNA expression levels in liver of Pepck, G6Pase, Cpt1, Acadm, and Scd1 measured by quantitative RT-PCR in Mstn+/+ and Mstn−/− mice on standard chow or HFD. (B) Serum glucagon, (C) lactate, and (D) β-hydroxybutyrate levels in Mstn+/+ and Mstn−/− mice on standard chow and HFD. n = 6–12. *P<0.05, **P<0.01.
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pone-0004937-g006: Adaptation to increased muscle mass.(A) Relative mRNA expression levels in liver of Pepck, G6Pase, Cpt1, Acadm, and Scd1 measured by quantitative RT-PCR in Mstn+/+ and Mstn−/− mice on standard chow or HFD. (B) Serum glucagon, (C) lactate, and (D) β-hydroxybutyrate levels in Mstn+/+ and Mstn−/− mice on standard chow and HFD. n = 6–12. *P<0.05, **P<0.01.

Mentions: We next asked whether Mstn−/− mice have similar metabolic responses to increased muscle mass as HFD-fed mice expressing a muscle-specific inducible constitutively active Akt1 transgene. First, we examined Mstn−/− mice for evidence of an increase in gluconeogenesis and glycolysis relative to control mice. Constitutively active Akt1 mice have an increase in expression in liver of genes encoding enzymes involved in gluconeogenesis, phosphoenolpyruvate carboxykinase (Pepck) and glucose 6-phosphatase (G6Pase), and an increase in serum levels of glucagon, which stimulates gluconeogenesis [29]. We found an increase in expression of Pepck in the liver of Mstn−/− mice relative to control littermates on standard chow but not HFD (Fig. 6A). The expression of Pepck in Mstn+/+ mice on HFD was significantly higher than in Mstn+/+ mice on standard chow (Fig. 6A). Mstn−/− mice, however, did not have increased expression of Pepck when fed a HFD relative to standard chow (Fig. 6A). There was no statistically significant difference in the expression of G6Pase in liver between genotypes on either diet although the level of G6Pase expression appeared to be higher in Mstn−/− mice than in controls on standard chow (Fig. 6A). Furthermore, there was no difference in serum glucagon levels between Mstn+/+ and Mstn−/− mice on standard chow or HFD (Fig. 6B) or in basal endogenous glucose production on standard chow as measured prior to insulin infusion during the hyperinsulinemic-euglycemic clamp experiment (89±21 µmol/kg/minute in Mstn−/− mice vs. 103±15 µmol/kg/minute in Mstn+/+ mice). Constitutively active Akt1 transgenic mice fed a HFD also have an increase in serum lactate levels, the end product of anaerobic glycolysis, but Mstn−/− mice did not have increased serum lactate levels compared to Mstn+/+ mice on either diet (Fig. 6C).


Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity.

Guo T, Jou W, Chanturiya T, Portas J, Gavrilova O, McPherron AC - PLoS ONE (2009)

Adaptation to increased muscle mass.(A) Relative mRNA expression levels in liver of Pepck, G6Pase, Cpt1, Acadm, and Scd1 measured by quantitative RT-PCR in Mstn+/+ and Mstn−/− mice on standard chow or HFD. (B) Serum glucagon, (C) lactate, and (D) β-hydroxybutyrate levels in Mstn+/+ and Mstn−/− mice on standard chow and HFD. n = 6–12. *P<0.05, **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654157&req=5

pone-0004937-g006: Adaptation to increased muscle mass.(A) Relative mRNA expression levels in liver of Pepck, G6Pase, Cpt1, Acadm, and Scd1 measured by quantitative RT-PCR in Mstn+/+ and Mstn−/− mice on standard chow or HFD. (B) Serum glucagon, (C) lactate, and (D) β-hydroxybutyrate levels in Mstn+/+ and Mstn−/− mice on standard chow and HFD. n = 6–12. *P<0.05, **P<0.01.
Mentions: We next asked whether Mstn−/− mice have similar metabolic responses to increased muscle mass as HFD-fed mice expressing a muscle-specific inducible constitutively active Akt1 transgene. First, we examined Mstn−/− mice for evidence of an increase in gluconeogenesis and glycolysis relative to control mice. Constitutively active Akt1 mice have an increase in expression in liver of genes encoding enzymes involved in gluconeogenesis, phosphoenolpyruvate carboxykinase (Pepck) and glucose 6-phosphatase (G6Pase), and an increase in serum levels of glucagon, which stimulates gluconeogenesis [29]. We found an increase in expression of Pepck in the liver of Mstn−/− mice relative to control littermates on standard chow but not HFD (Fig. 6A). The expression of Pepck in Mstn+/+ mice on HFD was significantly higher than in Mstn+/+ mice on standard chow (Fig. 6A). Mstn−/− mice, however, did not have increased expression of Pepck when fed a HFD relative to standard chow (Fig. 6A). There was no statistically significant difference in the expression of G6Pase in liver between genotypes on either diet although the level of G6Pase expression appeared to be higher in Mstn−/− mice than in controls on standard chow (Fig. 6A). Furthermore, there was no difference in serum glucagon levels between Mstn+/+ and Mstn−/− mice on standard chow or HFD (Fig. 6B) or in basal endogenous glucose production on standard chow as measured prior to insulin infusion during the hyperinsulinemic-euglycemic clamp experiment (89±21 µmol/kg/minute in Mstn−/− mice vs. 103±15 µmol/kg/minute in Mstn+/+ mice). Constitutively active Akt1 transgenic mice fed a HFD also have an increase in serum lactate levels, the end product of anaerobic glycolysis, but Mstn−/− mice did not have increased serum lactate levels compared to Mstn+/+ mice on either diet (Fig. 6C).

Bottom Line: To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle.We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet.In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity.

View Article: PubMed Central - PubMed

Affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn(-/-) mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn(-/-) mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn(-/-) mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn(-/-) mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn(-/-) mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn(-/-) mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes.

Show MeSH
Related in: MedlinePlus