Limits...
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.

Show MeSH

Related in: MedlinePlus

Effects of Mstn disruption on body fat accumulation in Ldlr−/− mice. A: Representative gross appearance (top panel) and micro-CT image of visceral and subcutaneous fat (bottom panel) of mice after 12 weeks of HFD (HF-diet). c, cecum; vf, visceral fat, sf, subcutaneous fat. B: NMR analysis of total fat at baseline (time 0) and after 5 and 10 weeks of HFD. Mstn+/+/Ldlr+/+, ♦; Mstn+/+/Ldlr−/−, ○; Mstn+−/Ldlr−/−, ▲; Mstn+−/Ldlr−/−, ●. C: Inguinal, epididymal, perirenal, and intrascapular brown fat weights of mice after 12 weeks of HFD. D: Representative gross appearance of hind-limb muscles (left panel) and quadriceps muscle weights (right panel) of mice after 12 weeks of HFD. ++/++, Mstn+/+/Ldlr+/+. ++/−−, Mstn+/+/Ldlr−/−. +−/−−, Mstn+−/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. Data are expressed as means ± SE (n = 11–21). **P < 0.01 compared with all other genotypes. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2712781&req=5

Figure 1: Effects of Mstn disruption on body fat accumulation in Ldlr−/− mice. A: Representative gross appearance (top panel) and micro-CT image of visceral and subcutaneous fat (bottom panel) of mice after 12 weeks of HFD (HF-diet). c, cecum; vf, visceral fat, sf, subcutaneous fat. B: NMR analysis of total fat at baseline (time 0) and after 5 and 10 weeks of HFD. Mstn+/+/Ldlr+/+, ♦; Mstn+/+/Ldlr−/−, ○; Mstn+−/Ldlr−/−, ▲; Mstn+−/Ldlr−/−, ●. C: Inguinal, epididymal, perirenal, and intrascapular brown fat weights of mice after 12 weeks of HFD. D: Representative gross appearance of hind-limb muscles (left panel) and quadriceps muscle weights (right panel) of mice after 12 weeks of HFD. ++/++, Mstn+/+/Ldlr+/+. ++/−−, Mstn+/+/Ldlr−/−. +−/−−, Mstn+−/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. Data are expressed as means ± SE (n = 11–21). **P < 0.01 compared with all other genotypes. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Ldlr−/− mice with varying Mstn genotypes, wild type (Mstn+/+/Ldlr−/−), heterozygous deletion (Mstn+/−/Ldlr−/−), and homozygous deletion (Mstn−/−/Ldlr−/−), were fed HFD for 11–12 weeks. Mstn+/+/Ldlr−/− controls demonstrated substantial gains in body weight, whole body fat mass (measured by NMR), and visceral and subcutaneous fat mass (measured by micro-CT scan). In contrast, Mstn−/−/Ldlr−/− mice resisted weight gain and accumulation of whole body and visceral fat mass in response to HFD (Fig. 1A and B, supplementary Fig. 1A and B, available in an online appendix). In agreement with the in vivo NMR data, the wet weights of the major fat depots (inguinal, epididymal, perirenal, as well as the interscapular brown fat) were significantly lower in the Mstn−/−/Ldlr−/− mice, as compared with wild-type, Mstn+/+/Ldlr−/−, and Mstn+/−/Ldlr−/− mice (Fig. 1C). Thus, Mstn−/−/Ldlr−/− mice are resistant to fat accumulation in all fat depots including the visceral and subcutaneous fat depot.


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 disruption on body fat accumulation in Ldlr−/− mice. A: Representative gross appearance (top panel) and micro-CT image of visceral and subcutaneous fat (bottom panel) of mice after 12 weeks of HFD (HF-diet). c, cecum; vf, visceral fat, sf, subcutaneous fat. B: NMR analysis of total fat at baseline (time 0) and after 5 and 10 weeks of HFD. Mstn+/+/Ldlr+/+, ♦; Mstn+/+/Ldlr−/−, ○; Mstn+−/Ldlr−/−, ▲; Mstn+−/Ldlr−/−, ●. C: Inguinal, epididymal, perirenal, and intrascapular brown fat weights of mice after 12 weeks of HFD. D: Representative gross appearance of hind-limb muscles (left panel) and quadriceps muscle weights (right panel) of mice after 12 weeks of HFD. ++/++, Mstn+/+/Ldlr+/+. ++/−−, Mstn+/+/Ldlr−/−. +−/−−, Mstn+−/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. Data are expressed as means ± SE (n = 11–21). **P < 0.01 compared with all other genotypes. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2712781&req=5

Figure 1: Effects of Mstn disruption on body fat accumulation in Ldlr−/− mice. A: Representative gross appearance (top panel) and micro-CT image of visceral and subcutaneous fat (bottom panel) of mice after 12 weeks of HFD (HF-diet). c, cecum; vf, visceral fat, sf, subcutaneous fat. B: NMR analysis of total fat at baseline (time 0) and after 5 and 10 weeks of HFD. Mstn+/+/Ldlr+/+, ♦; Mstn+/+/Ldlr−/−, ○; Mstn+−/Ldlr−/−, ▲; Mstn+−/Ldlr−/−, ●. C: Inguinal, epididymal, perirenal, and intrascapular brown fat weights of mice after 12 weeks of HFD. D: Representative gross appearance of hind-limb muscles (left panel) and quadriceps muscle weights (right panel) of mice after 12 weeks of HFD. ++/++, Mstn+/+/Ldlr+/+. ++/−−, Mstn+/+/Ldlr−/−. +−/−−, Mstn+−/Ldlr−/−. −−/−−, Mstn−/−/Ldlr−/−. Data are expressed as means ± SE (n = 11–21). **P < 0.01 compared with all other genotypes. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Ldlr−/− mice with varying Mstn genotypes, wild type (Mstn+/+/Ldlr−/−), heterozygous deletion (Mstn+/−/Ldlr−/−), and homozygous deletion (Mstn−/−/Ldlr−/−), were fed HFD for 11–12 weeks. Mstn+/+/Ldlr−/− controls demonstrated substantial gains in body weight, whole body fat mass (measured by NMR), and visceral and subcutaneous fat mass (measured by micro-CT scan). In contrast, Mstn−/−/Ldlr−/− mice resisted weight gain and accumulation of whole body and visceral fat mass in response to HFD (Fig. 1A and B, supplementary Fig. 1A and B, available in an online appendix). In agreement with the in vivo NMR data, the wet weights of the major fat depots (inguinal, epididymal, perirenal, as well as the interscapular brown fat) were significantly lower in the Mstn−/−/Ldlr−/− mice, as compared with wild-type, Mstn+/+/Ldlr−/−, and Mstn+/−/Ldlr−/− mice (Fig. 1C). Thus, Mstn−/−/Ldlr−/− mice are resistant to fat accumulation in all fat depots including the visceral and subcutaneous fat depot.

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