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

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 delta (PPAR-delta) 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-delta-deficient mice. Administration of telmisartan up-regulated levels of PPAR-delta and phospho-AMPK alpha in cultured myotubes. However, PPAR-delta gene deficiency completely abolished the telmisartan effect on phospho-AMPK alpha in 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-delta-deficient mice. The mechanism is involved in PPAR-delta-mediated stimulation of the AMPK pathway. Compared to the control mice, phospho-AMPK alpha level in skeletal muscle was up-regulated in mice treated with telmisartan. In contrast, phospho-AMPK alpha expression in skeletal muscle was unchanged in PPAR-delta-deficient mice treated with telmisartan. These findings highlight the ability of telmisartan to improve skeletal muscle function, and they implicate PPAR-delta as a potential therapeutic target for the prevention of type 2 diabetes.