Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

Abstract

Background/Aims: Skeletal muscle atrophy is an important health issue and can impose tremendous economic burdens on healthcare systems. Glucocorticoids (GCs) are well-known factors that result in muscle atrophy observed in numerous pathological conditions. Therefore, the development of effective and safe therapeutic strategies for GC-induced muscle atrophy has significant clinical implications. Some natural compounds have been shown to effectively prevent muscle atrophy under several wasting conditions. Dihydromyricetin (DM), the most abundant flavonoid in Ampelopsis grossedentata, has a broad range of health benefits, but its effects on muscle atrophy are unclear. The purpose of this study was to evaluate the effects and underlying mechanisms of DM on muscle atrophy induced by the synthetic GC dexamethasone (Dex). Methods: The effects of DM on Dex-induced muscle atrophy were assessed in Sprague-Dawley rats and L6 myotubes. Muscle mass and myofiber cross-sectional areas were analyzed in gastrocnemius muscles. Muscle function was evaluated by a grip strength test. Myosin heavy chain (MHC) content and myotube diameter were measured in myotubes. Mitochondrial morphology was observed by transmission electron microscopy and confocal laser scanning microscopy. Mitochondrial DNA (mtDNA) was quantified by real-time PCR. Mitochondrial respiratory chain complex activities were examined using the MitoProfile Rapid Microplate Assay Kit, and mitochondrial membrane potential was assessed by JC-1 staining. Protein levels of mitochondrial biogenesis and dynamics markers were detected by western blotting. Myotubes were transfected with siRNAs targeting peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), mitochondrial transcription factor A (TFAM) and mitofusin-2 (mfn2) to determine the underlying mechanisms. Results: In vivo, DM preserved muscles from weight and average fiber cross-sectional area losses and improved grip strength. In vitro, DM prevented the decrease in MHC content and myotube diameter. Moreover, DM stimulated mitochondrial biogenesis and promoted mitochondrial fusion, rescued the reduced mtDNA content, improved mitochondrial morphology, prevented the collapse in mitochondrial membrane potential and enhanced mitochondrial respiratory chain complex activities; these changes restored mitochondrial function and improved protein metabolism, contributing to the prevention of Dex-induced muscle atrophy. Furthermore, the protective effects of DM on mitochondrial function and muscle atrophy were alleviated by PGC-1α siRNA, TFAM siRNA and mfn2 siRNA transfection in vitro. Conclusion: DM attenuated Dex-induced muscle atrophy by reversing mitochondrial dysfunction, which was partially mediated by the PGC-1α/TFAM and PGC-1α/mfn2 signaling pathways. Our findings may open new avenues for identifying natural compounds that improve mitochondrial function as promising candidates for the management of muscle atrophy.

Flavonoids and Mitochondria: Activation of Cytoprotective Pathways?

“…One of the important effects of kaempferol in the neuronal ischemic stroke model was the suppression of DRP1 activation [194]. Dihydromyricetin attenuated dexamethasone-induced muscle atrophy by sustaining mitochondrial function, among other effects, inducing fusion by stimulating MFN2 expression [195]. Additionally, puerarin and quercetogetin have been described to protect cells against palmitate-and cigarette smoke extract-induced mitochondrial dysfunction by regulating mitochondrial dynamics [183,196].…”

Dihydromyricetin Protects Against Gentamicin-Induced Ototoxicity via PGC-1α/SIRT3 Signaling in vitro

“…However, the mechanism by which DHM regulates SIRT3 has not been reported. In previous studies, DHM was found to increase the expression of PGC-1α in skeletal muscle (Zhou et al, 2015;Huang et al, 2018). PGC-1α is a transcription factor that regulates lipid metabolism by inducing the expression of multiple genes in the tricarboxylic acid cycle and mitochondrial fatty acid oxidation pathway (Cheng et al, 2018).…”

Effects of Fish Meat-derived Peptide and Dipeptides on Dexamethasone-induced Fatigue in Mice

“…However, oxidative stress mainly promotes via the activation of p38 mitogen-activated protein kinase, which subsequently induces the expression of atrogin-1, MuRF1 and the autophagy-lysosome system [24,25]. Moreover, it also has been reported that DEX-induced muscle atrophy is partially caused by mitochondrial dysfunction mediated by the PGC-1α/TFAM and PGC-1α/mfn2 signaling pathways [11]. The mechanism through which FMDP suppresses DEX-induced fatigue is not clarified in this study.…”

“…With the increasing use of glucocorticoids to treat inflammatory diseases, exogenous glucocorticoids have become the most common cause of drug-induced muscle wasting, which is a clinical problem [10]. Recently, Huang et al indicated that dexamethasone (DEX) elevates oxidative stress markers, protein carbonyl levels and malondialdehyde content (lipid peroxidation) in skeletal muscle which resulted in mitochondrial dysfunction [11].…”