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An Increase in Murine Skeletal Muscle Peroxisome Proliferator-Activated Receptor- Coactivator-1 (PGC-1) mRNA in Response to Exercise Is Mediated by ß-Adrenergic Receptor Activation

Nutritional Science Program, National Institute of Health and Nutrition (S.M., Y.K., M.T., O.E.), Tokyo 162-8636, Japan; Department of Health and Nutrition, Niigata University of Health and Welfare (K.K.), Niigata 950-3198, Japan; Molecular Medicine Research Labs (M.G.), Astellas Pharma Inc., Tsukuba 305-8585, Japan; and Division of Endocrinology and Metabolism, National Institute for Physiological Sciences and the Graduate University for Advanced Studies (T.S., Y.M.), Okazaki 444-8585, Japan

Address all correspondence and requests for reprints to: Shinji Miura, Ph.D., or Osamu Ezaki, M.D., National Institute of Health and Nutrition, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8636, Japan. E-mail: shinjim{at}nih.go.jp or ezaki{at}nih.go.jp.

A single bout of exercise increases expression of peroxisome proliferator-activated receptor- coactivator (PGC)-1 mRNA, which may promote mitochondrial biogenesis in skeletal muscle. In brown adipose tissue, cold exposure up-regulates PGC-1 expression via adrenergic receptor (AR) activation. Because exercise also activates the sympathetic nervous system, we examined whether exercise-induced increase in PGC-1 mRNA expression in skeletal muscle was mediated via AR activation. In C57BL/6J mice, injection of the ß2-AR agonist clenbuterol, but not -, ß1-, or ß3-AR agonists, increased PGC-1 mRNA expression more than 30-fold in skeletal muscle. The clenbuterol-induced increase in PGC-1 mRNA expression in mice was inhibited by pretreatment with the ß-AR antagonist propranolol. In ex vivo experiments, direct exposure of rat epitrochlearis to ß2-AR agonist, but not -, ß1-, and ß3-AR agonist, led to an increase in levels of PGC-1 mRNA. Injection of ß2-AR agonist did not increase PGC-1 mRNA expression in ß1-, ß2-, and ß3-AR knockout mice (ß-less mice). PGC-1 mRNA in gastrocnemius was increased 3.5-fold in response to running on a treadmill for 45 min. The exercise-induced increase in PGC-1 mRNA was inhibited by approximately 70% by propranolol or the ß2-AR-specific inhibitor ICI 118,551. The exercise-induced increase in PGC-1 mRNA in ß-less mice was also 36% lower than that in wild-type mice. These data indicate that up-regulation of PGC-1 expression in skeletal muscle by exercise is mediated, at least in part, by ß-ARs activation. Among ARs, ß2-AR may mediate an increase in PGC-1 by exercise.