ATP-Sensitive K+ Channel Knockout Compromises the Metabolic Benefit of Exercise Training, Resulting in Cardiac Deficits

  1. Garvan C. Kane1,
  2. Atta Behfar1,
  3. Satsuki Yamada1,
  4. Carmen Perez-Terzic12,
  5. Fearghas O’Cochlain1,
  6. Santiago Reyes1,
  7. Petras P. Dzeja1,
  8. Takashi Miki3,
  9. Susumu Seino3 and
  10. Andre Terzic1
  1. 1Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota
  2. 2Department of Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota
  3. 3Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
  1. Address correspondence and reprint requests to Andre Terzic, Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905. E-mail: terzic.andre{at}mayo.edu

Abstract

Exercise training elicits a metabolic and cardiovascular response that underlies fitness. The molecular mechanisms that orchestrate this adaptive response and secure the wide-ranging gains of a regimented exercise program are poorly understood. Formed through association of the Kir6.2 pore and the sulfonylurea receptor, the stress-responsive ATP-sensitive K+ channels (KATP channels), with their metabolic-sensing capability and broad tissue expression, are potential candidates for integrating the systemic adaptive response to repetitive exercise. Here, the responses of mice lacking functional Kir6.2-containing KATP channels (Kir6.2-KO) were compared with wild-type controls following a 28-day endurance swimming protocol. While chronic aquatic training resulted in lighter, leaner, and fitter wild-type animals, the Kir6.2-KO manifested less augmentation in exercise capacity and lacked metabolic improvement in body fat composition and glycemic handling with myocellular defects. Moreover, the repetitive stress of swimming unmasked a survival disadvantage in the Kir6.2-KO, associated with pathologic calcium-dependent structural damage in the heart and impaired cardiac performance. Thus, Kir6.2-containing KATP channel activity is required for attainment of the physiologic benefits of exercise training without injury.

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted May 21, 2004.
    • Received March 12, 2004.
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