Protective Effects of the Chalcone-Based Derivative AN07 on Inflammation-Associated Myotube Atrophy Induced by Lipopolysaccharide

• Published in: International journal of molecular sciences Vol. 23; no. 21; p. 12929
• Main Authors: Fang, Wei-Yu, Lin, Chih-Lung, Chang, Wan-Hsuan, Chang, Chih-Hsiang, Huang, Yun-Cian, Tsai, Yi-Hong, Chang, Fang-Rong, Lo, Yi-Ching
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.11.2022; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Alzheimer's disease; Antioxidants; Atrophy; Attenuation; Autophagy; Catabolism; chalcone; Coronaviruses; COVID-19; Cytotoxicity; Degradation; Enzymes; Gene expression; Homeostasis; Inflammation; Insulin; Insulin-like growth factor I; Insulin-like growth factors; Kinases; Lipopolysaccharides; Lysosomal protein; Membrane potential; Metabolism; Mitochondria; mitochondrial oxygen consumption; Muscles; Musculoskeletal system; myotube; Myotubes; Neuroprotection; NF-κB protein; NOX4 protein; Oxidation; Oxidative stress; Oxygen consumption; Peroxisome proliferator-activated receptors; Phagocytosis; Prostaglandin E2; Proteasomes; Protein biosynthesis; Protein expression; Protein synthesis; protein synthesis/degradation; Proteins; Respiration; Skeletal muscle; Tumor necrosis factor-α
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232112929

Inflammation is a major cause of skeletal muscle atrophy in various diseases. 2-Hydroxy-4′-methoxychalcone (AN07) is a chalcone-based peroxisome-proliferator-activated receptor gamma (PPARγ) agonist with various effects, such as antiatherosclerosis, anti-inflammation, antioxidative stress, and neuroprotection. In this study, we examined the effects of AN07 on protein homeostasis pathway and mitochondrial function in inflammation-associated myotube atrophy induced by lipopolysaccharides (LPS). We found that AN07 significantly attenuated NF-κB activation, inflammatory factors (TNF-α, IL-1β, COX-2, and PGE2), Nox4 expression, and reactive oxygen species levels in LPS-treated C2C12 myotubes. Moreover, AN07 increased SOD2 expression and improved mitochondrial function, including mitochondrial membrane potential and mitochondrial oxygen consumption rate. We also demonstrated that AN07 attenuated LPS-induced reduction of myotube diameter, MyHC expression, and IGF-1/IGF-1R/p-Akt-mediated protein synthesis signaling. Additionally, AN07 downregulated LPS-induced autophagy–lysosomal protein degradation molecules (LC3-II/LC3-I and degraded p62) and ubiquitin–proteasome protein degradation molecules (n-FoxO1a/MuRF1/atrogin-1). However, the regulatory effects of AN07 on protein synthesis and degradation signaling were inhibited by the IGF-1R inhibitor AG1024 and the PI3K inhibitor wortmannin. In addition, the PPARγ antagonist GW9662 attenuated the effects of AN07 against LPS-induced inflammation, oxidation, and protein catabolism. In conclusion, our findings suggest that AN07 possesses protective effects on inflammation-induced myotube atrophy and mitochondrial dysfunction.