Role of β-adrenergic signaling in masseter muscle

by Aiko Ito, Yoshiki Ohnuki, Kenji Suita, Misao Ishikawa, Yasumasa Mototani, Kouichi Shiozawa, Naoya Kawamura, Yuka Yagisawa, Megumi Nariyama, Daisuke Umeki, Yoshiki Nakamura, Satoshi Okumura

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.