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Genetic disruption of myostatin reduces the development of proatherogenic dyslipidemia and atherogenic lesions in Ldlr mice.

Tu P, Bhasin S, Hruz PW, Herbst KL, Castellani LW, Hua N, Hamilton JA, Guo W - Diabetes (2009)

Bottom Line: Insulin-resistant states, such as obesity and type 2 diabetes, contribute substantially to accelerated atherogenesis.Null mutations of myostatin (Mstn) are associated with increased muscle mass and decreased fat mass.Myostatin may be a useful target for drug development for prevention and treatment of obesity and its associated type 2 diabetes and atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

ABSTRACT

Objective: Insulin-resistant states, such as obesity and type 2 diabetes, contribute substantially to accelerated atherogenesis. Null mutations of myostatin (Mstn) are associated with increased muscle mass and decreased fat mass. In this study, we determined whether Mstn disruption could prevent the development of insulin resistance, proatherogenic dyslipidemia, and atherogenesis.

Research design and methods: C57BL/6 Ldlr(-/-) mice were cross-bred with C57BL/6 Mstn(-/-) mice for >10 generations to generate Mstn(-/-)/Ldlr(-/-) double-knockout mice. The effects of high-fat/high-cholesterol diet on body composition, plasma lipids, systemic and tissue-specific insulin sensitivity, hepatic steatosis, as well as aortic atheromatous lesion were characterized in Mstn(-/-)/Ldlr(-/-) mice in comparison with control Mstn(+/+)/Ldlr(-/-) mice.

Results: Compared with Mstn(+/+)/Ldlr(-/-) controls, Mstn(-/-)/ Ldlr(-/-) mice were resistant to diet-induced obesity, and had greatly improved insulin sensitivity, as indicated by 42% higher glucose infusion rate and 90% greater muscle [(3)H]-2-deoxyglucose uptake during hyperinsulinemic-euglycemic clamp. Mstn(-/-)/Ldlr(-/-) mice were protected against diet-induced hepatic steatosis and had 56% higher rate of hepatic fatty acid beta-oxidation than controls. Mstn(-/-)/Ldlr(-/-) mice also had 36% lower VLDL secretion rate and were protected against diet-induced dyslipidemia, as indicated by 30-60% lower VLDL and LDL cholesterol, free fatty acids, and triglycerides. Magnetic resonance angiography and en face analyses demonstrated 41% reduction in aortic atheromatous lesions in Ldlr(-/-) mice with Mstn deletion.

Conclusions: Inactivation of Mstn protects against the development of insulin resistance, proatherogenic dyslipidemia, and aortic atherogenesis in Ldlr(-/-) mice. Myostatin may be a useful target for drug development for prevention and treatment of obesity and its associated type 2 diabetes and atherosclerosis.

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Atherogenic lipid profile in Ldlr−/− mice with Mstn deletion. A and B: Fasting plasma FFA, triglycerides, and cholesterol levels of mice at baseline (A) and after 10 weeks of HFD (HF-diet) (B). C and D: Lipoprotein profile in Mstn+/+/Ldlr−/− (○) and Mstn−/−/Ldlr−/− (●) mice after 11 weeks of HFD. Data are presented as average cholesterol (C) and triglycerides (D) distribution for each group. E: Plasma apoA1- and apoB100-containing lipoprotein particles before and after induction of HFD. The graphs demonstrate the quantification of each molecule, displayed as apoB100/apoA1 ratio. Averages were taken from four different gels. Blood was drawn from mice after 10 weeks of HFD. ++/−−, Mstn+/+/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. Data are shown as the means ± SE (n = 7–10). *P < 0.05, **P < 0.01.
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Figure 3: Atherogenic lipid profile in Ldlr−/− mice with Mstn deletion. A and B: Fasting plasma FFA, triglycerides, and cholesterol levels of mice at baseline (A) and after 10 weeks of HFD (HF-diet) (B). C and D: Lipoprotein profile in Mstn+/+/Ldlr−/− (○) and Mstn−/−/Ldlr−/− (●) mice after 11 weeks of HFD. Data are presented as average cholesterol (C) and triglycerides (D) distribution for each group. E: Plasma apoA1- and apoB100-containing lipoprotein particles before and after induction of HFD. The graphs demonstrate the quantification of each molecule, displayed as apoB100/apoA1 ratio. Averages were taken from four different gels. Blood was drawn from mice after 10 weeks of HFD. ++/−−, Mstn+/+/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. Data are shown as the means ± SE (n = 7–10). *P < 0.05, **P < 0.01.

Mentions: Even before HFD induction, Mstn−/−/Ldlr−/− mice had significantly lower plasma triglycerides, free fatty acids (FFA), and total cholesterol levels compared with Mstn+/+/Ldlr−/− mice (Fig. 3A). After 10 weeks of HFD, Mstn+/+/Ldlr−/− controls displayed marked increase in plasma triglycerides (3.0-fold), FFA (2.3-fold), and cholesterol (3.8-fold) levels compared with baseline; the changes in plasma lipids were significantly greater than those observed in Mstn−/−/Ldlr−/− mice after HFD. Plasma triglycerides, FFA, and cholesterol levels after HFD were significantly lower in Mstn−/−/Ldlr−/− than in Mstn+/+/Ldlr−/− controls (Fig. 3B), suggesting that Mstn deletion protects against the development of proatherogenic dyslipidemia in Ldlr−/− mice fed HFD.


Genetic disruption of myostatin reduces the development of proatherogenic dyslipidemia and atherogenic lesions in Ldlr mice.

Tu P, Bhasin S, Hruz PW, Herbst KL, Castellani LW, Hua N, Hamilton JA, Guo W - Diabetes (2009)

Atherogenic lipid profile in Ldlr−/− mice with Mstn deletion. A and B: Fasting plasma FFA, triglycerides, and cholesterol levels of mice at baseline (A) and after 10 weeks of HFD (HF-diet) (B). C and D: Lipoprotein profile in Mstn+/+/Ldlr−/− (○) and Mstn−/−/Ldlr−/− (●) mice after 11 weeks of HFD. Data are presented as average cholesterol (C) and triglycerides (D) distribution for each group. E: Plasma apoA1- and apoB100-containing lipoprotein particles before and after induction of HFD. The graphs demonstrate the quantification of each molecule, displayed as apoB100/apoA1 ratio. Averages were taken from four different gels. Blood was drawn from mice after 10 weeks of HFD. ++/−−, Mstn+/+/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. Data are shown as the means ± SE (n = 7–10). *P < 0.05, **P < 0.01.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 3: Atherogenic lipid profile in Ldlr−/− mice with Mstn deletion. A and B: Fasting plasma FFA, triglycerides, and cholesterol levels of mice at baseline (A) and after 10 weeks of HFD (HF-diet) (B). C and D: Lipoprotein profile in Mstn+/+/Ldlr−/− (○) and Mstn−/−/Ldlr−/− (●) mice after 11 weeks of HFD. Data are presented as average cholesterol (C) and triglycerides (D) distribution for each group. E: Plasma apoA1- and apoB100-containing lipoprotein particles before and after induction of HFD. The graphs demonstrate the quantification of each molecule, displayed as apoB100/apoA1 ratio. Averages were taken from four different gels. Blood was drawn from mice after 10 weeks of HFD. ++/−−, Mstn+/+/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. Data are shown as the means ± SE (n = 7–10). *P < 0.05, **P < 0.01.
Mentions: Even before HFD induction, Mstn−/−/Ldlr−/− mice had significantly lower plasma triglycerides, free fatty acids (FFA), and total cholesterol levels compared with Mstn+/+/Ldlr−/− mice (Fig. 3A). After 10 weeks of HFD, Mstn+/+/Ldlr−/− controls displayed marked increase in plasma triglycerides (3.0-fold), FFA (2.3-fold), and cholesterol (3.8-fold) levels compared with baseline; the changes in plasma lipids were significantly greater than those observed in Mstn−/−/Ldlr−/− mice after HFD. Plasma triglycerides, FFA, and cholesterol levels after HFD were significantly lower in Mstn−/−/Ldlr−/− than in Mstn+/+/Ldlr−/− controls (Fig. 3B), suggesting that Mstn deletion protects against the development of proatherogenic dyslipidemia in Ldlr−/− mice fed HFD.

Bottom Line: Insulin-resistant states, such as obesity and type 2 diabetes, contribute substantially to accelerated atherogenesis.Null mutations of myostatin (Mstn) are associated with increased muscle mass and decreased fat mass.Myostatin may be a useful target for drug development for prevention and treatment of obesity and its associated type 2 diabetes and atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

ABSTRACT

Objective: Insulin-resistant states, such as obesity and type 2 diabetes, contribute substantially to accelerated atherogenesis. Null mutations of myostatin (Mstn) are associated with increased muscle mass and decreased fat mass. In this study, we determined whether Mstn disruption could prevent the development of insulin resistance, proatherogenic dyslipidemia, and atherogenesis.

Research design and methods: C57BL/6 Ldlr(-/-) mice were cross-bred with C57BL/6 Mstn(-/-) mice for >10 generations to generate Mstn(-/-)/Ldlr(-/-) double-knockout mice. The effects of high-fat/high-cholesterol diet on body composition, plasma lipids, systemic and tissue-specific insulin sensitivity, hepatic steatosis, as well as aortic atheromatous lesion were characterized in Mstn(-/-)/Ldlr(-/-) mice in comparison with control Mstn(+/+)/Ldlr(-/-) mice.

Results: Compared with Mstn(+/+)/Ldlr(-/-) controls, Mstn(-/-)/ Ldlr(-/-) mice were resistant to diet-induced obesity, and had greatly improved insulin sensitivity, as indicated by 42% higher glucose infusion rate and 90% greater muscle [(3)H]-2-deoxyglucose uptake during hyperinsulinemic-euglycemic clamp. Mstn(-/-)/Ldlr(-/-) mice were protected against diet-induced hepatic steatosis and had 56% higher rate of hepatic fatty acid beta-oxidation than controls. Mstn(-/-)/Ldlr(-/-) mice also had 36% lower VLDL secretion rate and were protected against diet-induced dyslipidemia, as indicated by 30-60% lower VLDL and LDL cholesterol, free fatty acids, and triglycerides. Magnetic resonance angiography and en face analyses demonstrated 41% reduction in aortic atheromatous lesions in Ldlr(-/-) mice with Mstn deletion.

Conclusions: Inactivation of Mstn protects against the development of insulin resistance, proatherogenic dyslipidemia, and aortic atherogenesis in Ldlr(-/-) mice. Myostatin may be a useful target for drug development for prevention and treatment of obesity and its associated type 2 diabetes and atherosclerosis.

Show MeSH
Related in: MedlinePlus