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 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.
Feng
Xiaoli
X
Centre for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
Luo
Zhidan
Z
Ma
Liqun
L
Ma
Shuangtao
S
Yang
Dachun
D
Zhao
Zhigang
Z
Yan
Zhencheng
Z
He
Hongbo
H
Cao
Tingbing
T
Liu
Daoyan
D
Zhu
Zhiming
Z
D000263:Adenylate Kinase / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism* / Q000627:therapeutic use; D001565:Benzoates / Q000378:metabolism* / Q000627:therapeutic use; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D010807:Physical Endurance / Q000502:physiology*; D012420:Running / Q000502:physiology*; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D047494:PPAR delta; D000263:Adenylate Kinase; D000077333:Telmisartan