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

Abstract

A single bout of exercise increases expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha mRNA, which may promote mitochondrial biogenesis in skeletal muscle. In brown adipose tissue, cold exposure up-regulates PGC-1alpha expression via adrenergic receptor (AR) activation. Because exercise also activates the sympathetic nervous system, we examined whether exercise-induced increase in PGC-1alpha mRNA expression in skeletal muscle was mediated via AR activation. In C57BL/6J mice, injection of the beta2-AR agonist clenbuterol, but not alpha-, beta1-, or beta3-AR agonists, increased PGC-1alpha mRNA expression more than 30-fold in skeletal muscle. The clenbuterol-induced increase in PGC-1alpha mRNA expression in mice was inhibited by pretreatment with the beta-AR antagonist propranolol. In ex vivo experiments, direct exposure of rat epitrochlearis to beta2-AR agonist, but not alpha-, beta1-, and beta3-AR agonist, led to an increase in levels of PGC-1alpha mRNA. Injection of beta2-AR agonist did not increase PGC-1alpha mRNA expression in beta1-, beta2-, and beta3-AR knockout mice (beta-less mice). PGC-1alpha mRNA in gastrocnemius was increased 3.5-fold in response to running on a treadmill for 45 min. The exercise-induced increase in PGC-1alpha mRNA was inhibited by approximately 70% by propranolol or the beta2-AR-specific inhibitor ICI 118,551. The exercise-induced increase in PGC-1alpha mRNA in beta-less mice was also 36% lower than that in wild-type mice. These data indicate that up-regulation of PGC-1alpha expression in skeletal muscle by exercise is mediated, at least in part, by beta-ARs activation. Among ARs, beta2-AR may mediate an increase in PGC-1alpha by exercise.

PGC-1α Mediated Muscle Aerobic Adaptations to Exercise, Heat and Cold Exposure

“…At rest, treatments with selective β-adrenergic agonist/antagonist have shown to induce or inhibit PGC-1α expression in rodents, respectively (Miura et al, 2007). Moreover in rodents, treatment with β-adrenergic antagonists have shown to attenuate the increase in PGC-1α mRNA following acute exercise (Miura et al, 2007) and mitochondrial biogenesis following endurance training (Ji et al, 1986). These studies support the findings by Puigserver et al (1998) and implicate adrenergic mechanisms in the regulation of PGC-1α and mitochondrial biogenesis.…”

“…It is further hypothesised that CREB directly induces the expression of PGC-1α by binding to the PGC-1α promoter region (Puigserver & Spiegelman, 2003;Puigserver et al, 1998;Wu et al, 1999). At rest, treatments with selective β-adrenergic agonist/antagonist have shown to induce or inhibit PGC-1α expression in rodents, respectively (Miura et al, 2007). Moreover in rodents, treatment with β-adrenergic antagonists have shown to attenuate the increase in PGC-1α mRNA following acute exercise (Miura et al, 2007) and mitochondrial biogenesis following endurance training (Ji et al, 1986).…”

Effect of exercise intensity and AICAR on isoform-specific expressions of murine skeletal muscle PGC-1α mRNA: a role of β2-adrenergic receptor activation

“…In mice, low-intensity exercise (15 m/min for 45 min) or injection of the ␤ 2 -adrenergic receptor (AR) agonist clenbuterol increased PGC-1␣-b and PGC-1␣-c mRNA expression more than 40-fold, but not that of PGC-1␣-a, in skeletal muscle (25). The increase in PGC-1␣ mRNA expression was specific to ␤ 2 -AR; injection of ␣-, ␤ 1 -, or ␤ 3 -AR agonist did not increase PGC-1␣ mRNA expression (26). Increased expressions in skeletal muscles in response to exercise were inhibited by pretreatment with the ␤ 2 -AR-specific antagonist ICI 118551 or nonspecific ␤-AR antagonist propranolol (26).…”

Effects of β2-agonists and exercise on β2-adrenergic receptor signaling in skeletal muscles

“…These findings suggest that β2-agonist-and exercise-induced activation of p38γ MAPK are involved in the anabolic adaptation of slow-twitch muscles. Furthermore, Miura et al 4) have shown that an exercise-induced increase in peroxisome proliferator-activated receptor γ coactivatior 1α (PGC-1α) mRNA is mediated by β2-AR activation. In a more detailed investigation, it was shown that exercise stimulates PGC-1α transcription in skeletal muscle via activation of the p38 MAPK pathway 39) .…”

“…In contrast, endurance training results in increased mitochondrial density, capillary density, changes in key metabolic enzyme levels, and increased maximal oxygen uptake 2,3) . These adaptations of skeletal muscles to exercise are mediated, at least in part, by β2-adrenergic receptors (β2-ARs) 4) .…”