Angiotensin II receptor blocker telmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway

J Cell Mol Med. 2011 Jul;15(7):1572-81. doi: 10.1111/j.1582-4934.2010.01085.x. Epub 2010 May 14.

Abstract

Clinical trials have shown that angiotensin II receptor blockers reduce the new onset of diabetes in hypertensives; however, the underlying mechanisms remain unknown. We investigated the effects of telmisartan on peroxisome proliferator activated receptor γ (PPAR-δ) and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway in cultured myotubes, as well as on the running endurance of wild-type and PPAR-δ-deficient mice. Administration of telmisartan up-regulated levels of PPAR-δ and phospho-AMPKα in cultured myotubes. However, PPAR-δ gene deficiency completely abolished the telmisartan effect on phospho-AMPKαin vitro. Chronic administration of telmisartan remarkably prevented weight gain, enhanced running endurance and post-exercise oxygen consumption, and increased slow-twitch skeletal muscle fibres in wild-type mice, but these effects were absent in PPAR-δ-deficient mice. The mechanism is involved in PPAR-δ-mediated stimulation of the AMPK pathway. Compared to the control mice, phospho-AMPKα level in skeletal muscle was up-regulated in mice treated with telmisartan. In contrast, phospho-AMPKα expression in skeletal muscle was unchanged in PPAR-δ-deficient mice treated with telmisartan. These findings highlight the ability of telmisartan to improve skeletal muscle function, and they implicate PPAR-δ as a potential therapeutic target for the prevention of type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism*
  • Angiotensin II Type 1 Receptor Blockers / metabolism*
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Animals
  • Benzimidazoles / metabolism*
  • Benzimidazoles / therapeutic use
  • Benzoates / metabolism*
  • Benzoates / therapeutic use
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / drug therapy
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / physiology*
  • Oxygen Consumption / physiology
  • PPAR delta / genetics
  • PPAR delta / metabolism*
  • Physical Endurance / physiology*
  • Running / physiology*
  • Telmisartan

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Benzoates
  • PPAR delta
  • Adenylate Kinase
  • Telmisartan