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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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Effects of Mstn deletion on liver of Ldlr−/− mice. A: Hematoxylin and eosin (H&E) and Oil Red O staining of the liver of Mstn+/+/Ldlr−/− and Mstn−/−/Ldlr−/− mice after 12 weeks of HFD (HF-diet). B and C: mRNA expression of Srebf1 (B) and fatty acid synthase (Fasn) (C) in the liver of mice before and after 12 weeks of HFD. Values are expressed with respect to Mstn+/+/Ldlr−/− controls. D: Protein expression of fatty acid synthase. Averages were taken from three different gels. E: Plasma apoB100 at 0 and 180 min after injection of Triton WR1339, a lipoprotein lipase inhibitor. VLDL secretion is determined as percent increase of apoB100 from baseline. Averages were taken from three different gels. F: Akt serine-473 and GSKα/β serine-21/9 phosphorylation in the liver of mice after 12 weeks of HFD. The graphs demonstrate the quantification of phosphorylation of each molecule. ++/−−, Mstn+/+/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. AU, arbitrary units. Data are shown as the means ± SE (n = 7–10). *P < 0.05, **P < 0.01. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 5: Effects of Mstn deletion on liver of Ldlr−/− mice. A: Hematoxylin and eosin (H&E) and Oil Red O staining of the liver of Mstn+/+/Ldlr−/− and Mstn−/−/Ldlr−/− mice after 12 weeks of HFD (HF-diet). B and C: mRNA expression of Srebf1 (B) and fatty acid synthase (Fasn) (C) in the liver of mice before and after 12 weeks of HFD. Values are expressed with respect to Mstn+/+/Ldlr−/− controls. D: Protein expression of fatty acid synthase. Averages were taken from three different gels. E: Plasma apoB100 at 0 and 180 min after injection of Triton WR1339, a lipoprotein lipase inhibitor. VLDL secretion is determined as percent increase of apoB100 from baseline. Averages were taken from three different gels. F: Akt serine-473 and GSKα/β serine-21/9 phosphorylation in the liver of mice after 12 weeks of HFD. The graphs demonstrate the quantification of phosphorylation of each molecule. ++/−−, Mstn+/+/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. AU, arbitrary units. Data are shown as the means ± SE (n = 7–10). *P < 0.05, **P < 0.01. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: The liver plays a leading role in systemic lipid homeostasis (25). In response to HFD feeding, the livers of Mstn+/+/Ldlr−/− mice displayed substantial fat accumulation (Fig. 5A). In contrast, Mstn−/−/Ldlr−/− mice had significantly lower hepatic triglyceride content, as well as total wet and dry liver weights (Fig. 5A; supplementary Fig. 4A, available in an online appendix). This protection against diet-induced hepatic fat infiltration in Mstn−/−/Ldlr−/− mice was associated with significant reduction in plasma adipose-derived FFA (Fig. 3A), glucose, and insulin (Fig. 4A and B), as well as with diminished expression of lipogenic master gene, sterol regulatory element–binding transcription factor 1 (Srebf1), and its key downstream target, fatty acid synthase mRNA and protein (Fig. 5B–D).


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)

Effects of Mstn deletion on liver of Ldlr−/− mice. A: Hematoxylin and eosin (H&E) and Oil Red O staining of the liver of Mstn+/+/Ldlr−/− and Mstn−/−/Ldlr−/− mice after 12 weeks of HFD (HF-diet). B and C: mRNA expression of Srebf1 (B) and fatty acid synthase (Fasn) (C) in the liver of mice before and after 12 weeks of HFD. Values are expressed with respect to Mstn+/+/Ldlr−/− controls. D: Protein expression of fatty acid synthase. Averages were taken from three different gels. E: Plasma apoB100 at 0 and 180 min after injection of Triton WR1339, a lipoprotein lipase inhibitor. VLDL secretion is determined as percent increase of apoB100 from baseline. Averages were taken from three different gels. F: Akt serine-473 and GSKα/β serine-21/9 phosphorylation in the liver of mice after 12 weeks of HFD. The graphs demonstrate the quantification of phosphorylation of each molecule. ++/−−, Mstn+/+/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. AU, arbitrary units. Data are shown as the means ± SE (n = 7–10). *P < 0.05, **P < 0.01. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 5: Effects of Mstn deletion on liver of Ldlr−/− mice. A: Hematoxylin and eosin (H&E) and Oil Red O staining of the liver of Mstn+/+/Ldlr−/− and Mstn−/−/Ldlr−/− mice after 12 weeks of HFD (HF-diet). B and C: mRNA expression of Srebf1 (B) and fatty acid synthase (Fasn) (C) in the liver of mice before and after 12 weeks of HFD. Values are expressed with respect to Mstn+/+/Ldlr−/− controls. D: Protein expression of fatty acid synthase. Averages were taken from three different gels. E: Plasma apoB100 at 0 and 180 min after injection of Triton WR1339, a lipoprotein lipase inhibitor. VLDL secretion is determined as percent increase of apoB100 from baseline. Averages were taken from three different gels. F: Akt serine-473 and GSKα/β serine-21/9 phosphorylation in the liver of mice after 12 weeks of HFD. The graphs demonstrate the quantification of phosphorylation of each molecule. ++/−−, Mstn+/+/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. AU, arbitrary units. Data are shown as the means ± SE (n = 7–10). *P < 0.05, **P < 0.01. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: The liver plays a leading role in systemic lipid homeostasis (25). In response to HFD feeding, the livers of Mstn+/+/Ldlr−/− mice displayed substantial fat accumulation (Fig. 5A). In contrast, Mstn−/−/Ldlr−/− mice had significantly lower hepatic triglyceride content, as well as total wet and dry liver weights (Fig. 5A; supplementary Fig. 4A, available in an online appendix). This protection against diet-induced hepatic fat infiltration in Mstn−/−/Ldlr−/− mice was associated with significant reduction in plasma adipose-derived FFA (Fig. 3A), glucose, and insulin (Fig. 4A and B), as well as with diminished expression of lipogenic master gene, sterol regulatory element–binding transcription factor 1 (Srebf1), and its key downstream target, fatty acid synthase mRNA and protein (Fig. 5B–D).

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