Genetic Disruption of Myostatin Reduces the Development of Proatherogenic Dyslipidemia and Atherogenic Lesions In Ldlr Null Mice

  1. Powen Tu1,
  2. Shalender Bhasin1,2,
  3. Paul W. Hruz3,
  4. Karen L. Herbst4,
  5. Lawrence W. Castellani5,
  6. Ning Hua6,
  7. James A. Hamilton6 and
  8. Wen Guo2
  1. 1Department of Molecular Medicine, Boston University School of Medicine, Boston, Massachusetts;
  2. 2Section of Endocrinology, Diabetes, & Nutrition, Department of Medicine, Boston Medical Center, Boston, Massachusetts;
  3. 3Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri;
  4. 4Division of Endocrinology & Metabolism, University of California San Diego, San Diego, California;
  5. 5Departments of Medicine/Cardiology, University of California Los Angeles, Los Angeles, California;
  6. 6Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts.
  1. Corresponding author: Shalender Bhasin, bhasin{at}bu.edu.

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 [3H]-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 β-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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received March 6, 2009.
    • Accepted May 12, 2009.
  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

| Table of Contents

This Article

  1. Diabetes vol. 58 no. 8 1739-1748
  1. Online-Only Appendix
  2. All Versions of this Article:
    1. db09-0349v1
    2. 58/8/1739 most recent