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

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

SUBMITTER: Feng X

PROVIDER: S-EPMC3823201 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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

Feng Xiaoli X 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

Journal of cellular and molecular medicine 20100514 7

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 ...[more]

PMID: 20477906

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Project description:ObjectiveExercise is a critical component of a healthy lifestyle and a key strategy for the prevention and management of metabolic disease. Identifying molecular mechanisms underlying adaptation in response to chronic physical activity is of critical interest in metabolic physiology. Circadian rhythms broadly modulate metabolism, including muscle substrate utilization and exercise capacity. Here, we define the molecular and physiological changes induced across the daily cycle by voluntary low intensity daily exercise.MethodsWildtype C57BL6/J male and female mice were housed with or without access to a running wheel for six weeks. Maximum running speed was measured at four different zeitgeber times (ZTs, hours after lights on) using either electrical or manual stimulation to motivate continued running on a motorized treadmill. RNA isolated from plantaris muscles at six ZTs was sequenced to establish the impact of daily activity on genome-wide transcription. Patterns of gene expression were analyzed using Gene Set Enrichment Analysis (GSEA) and Detection of Differential Rhythmicity (DODR). Blood glucose, lactate, and ketones, and muscle and liver glycogen were measured before and after exercise.ResultsWe demonstrate that the use of mild electrical shocks to motivate running negatively impacts maximum running speed in mice, and describe a manual method to motivate running in rodent exercise studies. Using this method, we show that time of day influences the increase in exercise capacity afforded by six weeks of voluntary wheel running: when maximum running speed is measured at the beginning of the nighttime active period in mice, there is no measurable benefit from a history of daily voluntary running, while maximum increase in performance occurs at the end of the night. We show that daily voluntary exercise dramatically remodels the murine muscle circadian transcriptome. Finally, we describe daily rhythms in carbohydrate metabolism associated with the time-dependent response to moderate daily exercise in mice.ConclusionsCollectively, these data indicate that chronic nighttime physical activity dramatically remodels daily rhythms of murine muscle gene expression, which in turn support daily fluctuations in exercise performance.

Dataset Information

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

Publications

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

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