Date Published: April 15, 2019
Publisher: Public Library of Science
Author(s): Aiko Ito, Yoshiki Ohnuki, Kenji Suita, Misao Ishikawa, Yasumasa Mototani, Kouichi Shiozawa, Naoya Kawamura, Yuka Yagisawa, Megumi Nariyama, Daisuke Umeki, Yoshiki Nakamura, Satoshi Okumura, Xun Ai.
In skeletal muscle, the major isoform of β-adrenergic receptor (β-AR) is β2-AR and the minor isoform is β1-AR, which is opposite to the situation in cardiac muscle. Despite extensive studies in cardiac muscle, the physiological roles of the β-AR subtypes in skeletal muscle are not fully understood. Therefore, in this work, we compared the effects of chronic β1- or β2-AR activation with a specific β1-AR agonist, dobutamine (DOB), or a specific β2-AR agonist, clenbuterol (CB), on masseter and cardiac muscles in mice. In cardiac muscle, chronic β1-AR stimulation induced cardiac hypertrophy, fibrosis and myocyte apoptosis, whereas chronic β2-AR stimulation induced cardiac hypertrophy without histological abnormalities. In masseter muscle, however, chronic β1-AR stimulation did not induce muscle hypertrophy, but did induce fibrosis and apoptosis concomitantly with increased levels of p44/42 MAPK (ERK1/2) (Thr-202/Tyr-204), calmodulin kinase II (Thr-286) and mammalian target of rapamycin (mTOR) (Ser-2481) phosphorylation. On the other hand, chronic β2-AR stimulation in masseter muscle induced muscle hypertrophy without histological abnormalities, as in the case of cardiac muscle, concomitantly with phosphorylation of Akt (Ser-473) and mTOR (Ser-2448) and increased expression of microtubule-associated protein light chain 3-II, an autophagosome marker. These results suggest that the β1-AR pathway is deleterious and the β2-AR is protective in masseter muscle. These data should be helpful in developing pharmacological approaches for the treatment of skeletal muscle wasting and weakness.
Adrenergic receptors (ARs) belong to the guanine nucleotide-binding G-protein-coupled receptor (GPCR) family. Among them, β2-AR is the most abundant form in skeletal muscle, while β1-AR accounts for less than 10% of ARs, and there are small populations of α1-AR and β3-AR . In contrast, the predominant receptor subtype expressed in the heart is β1-AR, with approximately 20% of β2-AR .
In this study, we examined the effects of chronic β1-AR or β2-AR stimulation on cardiac and masseter muscles of mice, using a selective β1-AR agonist (DOB) and a selective β2-AR agonist (CB). We have demonstrated that activation of β1-AR signaling plays an important role in the development of myocyte apoptosis and fibrosis not only in cardiac muscle, but also in skeletal muscle.