Myricanol rescues dexamethasone‐induced muscle dysfunction via a sirtuin 1‐dependent mechanism

• Published in: Journal of cachexia, sarcopenia and muscle sarcopenia and muscle, 2019-04, Vol.10 (2), p.429-444
• Main Authors: Shen, Shengnan, Liao, Qiwen, Liu, Jingxin, Pan, Ruile, Lee, Simon Ming‐Yuen, Lin, Ligen
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - genetics; Atrophy; Autophagy; Autophagy - drug effects; Autophagy - genetics; Binding sites; Biomarkers; Biosynthesis; Biotechnology; Cell Line; Dexamethasone; Dexamethasone - adverse effects; Diarylheptanoids - chemistry; Diarylheptanoids - pharmacology; Disease Models, Animal; Gene Expression Regulation - drug effects; Kinases; Ligands; Mice; Models, Molecular; Molecular Conformation; Muscle atrophy; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle function; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiopathology; Muscular Atrophy - etiology; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Musculoskeletal system; Myricanol; Organelle Biogenesis; Original; Penicillin; PGC‐1α; Protein synthesis; Proteins; SIRT1; Sirtuin 1 - chemistry; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Steroids; Structure-Activity Relationship
• ISSN: 2190-5991; 2190-6009
• DOI: 10.1002/jcsm.12393

Background Muscle atrophy and weakness are adverse effects of high dose or the sustained usage of glucocorticoids. Loss of mitochondria and degradation of protein are highly correlated with muscle dysfunction. The deacetylase sirtuin 1 (SIRT1) plays a vital role in muscle remodelling. The current study was designed to identify myricanol as a SIRT1 activator, which could protect skeletal muscle against dexamethasone‐induced wasting. Methods The dexamethasone‐induced atrophy in C2C12 myotubes was evaluated by expression of myosin heavy chain, muscle atrophy F‐box (atrogin‐1), and muscle ring finger 1 (MuRF1), using western blots. The mitochondrial content and oxygen consumption were assessed by MitoTracker staining and extracellular flux analysis, respectively. Muscle dysfunction was established in male C57BL/6 mice (8–10 weeks old, n = 6) treated with a relatively high dose of dexamethasone (25 mg/kg body weight, i.p., 10 days). Body weight, grip strength, forced swimming capacity, muscle weight, and muscle histology were assessed. The expression of proteolysis‐related, autophagy‐related, apoptosis‐related, and mitochondria‐related proteins was analysed by western blots or immunoprecipitation. Results Myricanol (10 μM) was found to rescue dexamethasone‐induced muscle atrophy and dysfunction in C2C12 myotubes, indicated by increased expression of myosin heavy chain (0.33 ± 0.14 vs. 0.89 ± 0.21, *P