Activation of adiponectin receptors has negative impact on muscle mass in C2C12 myotubes and fast-type mouse skeletal muscle.

Rika Ito,Yoshitaka Ohno,Katsumasa Goto,Akihiro Ikuta,Masaki Higa,Ayumi Goto,Megumi Aoshima,Hirofumi Miyata,Tatsuro Egawa,Tatsuro Egawa,Kazuya Ohashi,Shingo Yokoyama,Atsushi Asakura

doi:10.1371/journal.pone.0205645

Rika Ito, Yoshitaka Ohno + Show 11 more

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https://doi.org/10.1371/journal.pone.0205645

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Abstract

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.

Highlights

IntroductionSkeletal muscle mass as well as function adapts to various extracellular and intracellular stimuli
AdipoRon-associated decrease in muscle protein content was partially rescued by knockdown of adiponectin receptor 1 (AdipoR1) and/or AdipoR2 (Fig 1B; effect of treatment, p
This study investigated the effects of AdipoRon on the protein content of C2C12 myotubes and mouse muscle mass of slow soleus muscle (SOL) and fast plantaris muscle (PLA)

Summary

Introduction

Skeletal muscle mass as well as function adapts to various extracellular and intracellular stimuli. Skeletal muscle atrophy is induced by inactivity, unloading, malnutrition as well as several diseases, including cancer, diabetes and heart failure [1,2]. Sarcopenia is well known as an aging-associated decline in skeletal muscle weakness accompanied with mass loss and dysfunction, resulting in impaired physical function [3]. The maintaining of skeletal muscle mass and function is a priority task in most countries with increasing populations have increasing percentages of large shares of adults aged 65 years and older, due to rising health-care cost [5,6]. The molecular mechanisms for aging-associated reductions in skeletal muscle mass remains unclear

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