This study investigated the effects of AdipoRon, which is an agonist for adiponectin receptor 1 (AdipoR1) and AdipoR2, on the protein content, myotube diameter, and number of nuclei per myotube of C2C12 cells and skeletal muscle mass in C57BL/6J mice. AdipoRon suppressed the protein content, myotube diameter, and number of nuclei per myotube of C2C12 cells of C2C12 myotubes in a dose-dependent manner. Adiponectin-associated decline of protein content, diameter, and number of nuclei per myotube in C2C12 myotubes was partially rescued by knockdown of AdipoR1 and/or AdipoR2. Phosphorylation level of AMPK showed a trend to be increased by AdipoRon. A significant increase in phosphorylation level of AMPK was observed at 20 μM AdipoRon. Knockdown of AdipoR1 and/or AdipoR2 rescued AdipoRon-associated decrease in protein content of C2C12 myotubes. AdipoRon-associated increase in phosphorylation level of AMPK in C2C12 myotubes was suppressed by knockdown of AdipoR1 and/or AdipoR2. Successive intravenous injections of AdipoRon into mice caused a decrease in the wet weight of plantaris muscle (PLA), but not in soleus muscle (SOL). Mean fiber cross-sectional area of PLA, but not of SOL, was significantly decreased by AdipoRon administration. On the one hand, the expression level of phosphorylated AMPK and ubiquitinated protein in SOL and PLA muscles was upregulated by AdipoRon administration. On the other hand, AdipoRon administration induced no changes in the expression level of puromycin-labeled proteins in both SOL and PLA muscles. Expression level of adiponectin in extensor digitorum longus (EDL) muscle was increased by aging, but not in SOL muscle. Aging had no effect on the expression level of AdipoR1 and AdipoR2 in both muscles. Phosphorylation level of AMPK in EDL was increased by aging, but not SOL muscle. Results from this study suggest that high level of circulating adiponectin may induce skeletal muscle atrophy, especially fast-type muscle.

Aging‐associated severe skeletal muscle atrophy, so‐called sarcopenia, is considered as a risk factor for falls in older adults. Recent cohort studies shows high circulating adiponectin levels predict decreased muscle strength among older adults. Adiponectin, one of adipokines, is exclusively synthesized in adipocytes, is secreted into circulation, binds to adiponectin receptors (AdRs), especially AdR1, and exhibits insulin‐sensitizing effects to stimulate the utilization of glucose and lipids in skeletal muscle cells. We hypothesize that high adiponectin levels may have atrophic effects on skeletal muscle cells. Therefore, this study investigated aging‐associated changes in adiponectin expression in skeletal muscle and effects of high adiponectin levels on myogenic differentiation. All procedures for animal experiments were carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health (Bethesda, MD, USA) and were approved by the Animal Use Committee of Toyohashi SOZO University. Aging‐associated up‐regulation of adiponectin in fast extensor digitorum longus muscle was observed. Agonist for AdRs, AdipoRon, suppressed myogenic differentiation of C2C12 cells in a dose‐dependent manner. Knockdown of AdR1 in C2C12 myoblasts induced by small interfering RNA (siRNA), partially depressed the AdipoRon‐induced suppression of C2C12 differentiation. Aging‐associated up‐regulation of adiponectin in skeletal muscle may induced muscle atrophy in especially fast skeletal muscle.Support or Funding InformationThis study was supported, in part, by Grants‐in‐Aid for challenging Exploratory Research (26560372), and Grants‐in‐Aid for Scientific Research (C, 26350818) from the Japan Society for the Promotion of Science, the Uehara Memorial Foundation, the Naito Foundation, Graduate School of Health Sciences, Toyohashi SOZO University, Descente Sports Foundation, and All Japan Coffee Association. No COI.