Preventive effect of dietary quercetin on disuse muscle atrophy by targeting mitochondria in denervated mice

Mukai, Rie; Matsui, Naoko; Fujikura, Yutaka; Matsumoto, Norifumi; Hou, De‐Xing; Kanzaki, Noriyuki; Shibata, Hiroshi; Horikawa, Manabu; Iwasa, Keiko; Hirasaka, Katsuya; Nikawa, Takeshi; Terao, Junji

doi:10.1016/j.jnutbio.2016.02.001

Cited by 60 publications

(48 citation statements)

References 52 publications

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“…Mitochondrial biogenesis is important for determining mitochondrial content and function, and compounds capable of stimulating mitochondrial biogenesis have shown potential as treatments for a wide range of diseases [56]. Quercetin and resveratrol can promote mitochondrial biogenesis and attenuate mitochondrial dysfunction in skeletal muscle during disuse-induced muscle atrophy [14,57]. Our previous study suggested that DM improved mitochondrial biogenesis in skeletal muscle via upregulation of the PGC-1α signaling pathway during hypobaric hypoxia conditions [25].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, several studies demonstrated that mitochondrial dysfunction precedes and activates muscle atrophy signaling in Dex-induced muscle atrophy models [12] and some natural plant extracts, including hydroxytyrosol acetate, resveratrol and quercetin, can target the mitochondria to improve mitochondrial function and prevent muscle atrophy under several wasting conditions [12][13][14]. Thus, development of drugs or nutrients that improve mitochondrial function could be beneficial in preventing Dex-induced muscle atrophy.…”

Section: Introductionmentioning

confidence: 99%

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

Huang¹,

Chen²,

Ren³

et al. 2018

Cell Physiol Biochem

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Huang¹,

Chen²,

Ren³

et al. 2018

Cell Physiol Biochem

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“…It is characterized by a decrease in the cross sectional area of the muscle, a decline in force generative capabilities, decrease in functional proteins of the muscle mass, and a loss of oxidative ability making the tissue less resistant to fatigue. There is a clear link in the literature with the dysfunction of the mitochondria and skeletal muscle atrophy (Kang et al, ; Mukai et al, ). The cause of both depends on the originating factor (disease, starvation, etc.…”

Section: Mitochondriamentioning

confidence: 99%

The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy

Theilen

Kunkel

Tyagi

2017

Journal Cellular Physiology

116

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Skeletal muscle atrophy is the consequence of protein degradation exceeding protein synthesis. This arises for a multitude of reasons including the unloading of muscle during microgravity, post-surgery bedrest, immobilization of a limb after injury, and overall disuse of the musculature. The development of therapies prior to skeletal muscle atrophy settings to diminish protein degradation is scarce. Mitochondrial dysfunction is associated with skeletal muscle atrophy and contributes to the induction of protein degradation and cell apoptosis through increased levels of ROS observed with the loss of organelle function. ROS binds mtDNA, leading to its degradation and decreasing functionality. Mitochondrial transcription factor A (TFAM) will bind and coat mtDNA, protecting it from ROS and degradation while increasing mitochondrial function. Exercise stimulates cell signaling pathways that converge on and increase PGC-1α, a well-known activator of the transcription of TFAM and mitochondrial biogenesis. Therefore, in the present review we are proposing, separately, exercise and TFAM treatments prior to atrophic settings (muscle unloading or disuse) alleviate skeletal muscle atrophy through enhanced mitochondrial adaptations and function. Additionally, we hypothesize the combination of exercise and TFAM leads to a synergistic effect in targeting mitochondrial function to prevent skeletal muscle atrophy.

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“…Quercetin and myricetin are the major flavonols from Chinese bayberry. Quercetin prevents muscle atrophy by targeting mitochondria in denervated mice model . Myricetin enhances mitochondrial activity by activating PGC‐1α and SIRT1, to improve physical endurance in mice .…”

Section: Introductionmentioning

confidence: 99%

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

Shen

Liao

Liu

et al. 2019

J cachexia sarcopenia muscle

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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 < 0.05), decreased expression of atrogin‐1 (2.31 ± 0.67 vs. 1.53 ± 0.25, * P < 0.05) and MuRF1 (1.55 ± 0.08 vs. 0.99 ± 0.12, ** P < 0.01), and elevated ATP production (3.83 ± 0.46 vs. 5.84 ± 0.79 nM/mg protein, ** P < 0.01), mitochondrial content (68.12 ± 10.07% vs. 116.38 ± 5.12%, * P < 0.05), and mitochondrial oxygen consumption (166.59 ± 22.89 vs. 223.77 ± 22.59 pmol/min, ** P < 0.01). Myricanol directly binds and activates SIRT1, with binding energy of −5.87 kcal/mol. Through activating SIRT1 deacetylation, myricanol inhibits forkhead box O 3a transcriptional activity to reduce protein degradation, induces autophagy to enhance degraded protein clearance, and increases peroxisome proliferator‐activated receptor γ coactivator‐1α activity to promote mitochondrial biogenesis. In dexamethasone‐induced muscle wasting C57BL/6 mice, 5 mg/kg myricanol treatment reduces the loss of muscle mass; the percentages of quadriceps and gastrocnemius muscle in myricanol‐treated mice are 1.36 ± 0.02% and 0.87 ± 0.08%, respectively (cf. 1.18 ± 0.06% and 0.78 ± 0.05% in dexamethasone‐treated mice, respectively). Myricanol also rescues dexamethasone‐induced muscle weakness, indicated by improved grip strength (70.90 ± 4.59 vs. 120.58 ± 7.93 g, ** P < 0.01) and prolonged swimming exhaustive time (48.80 ± 11.43 vs. 83.75 ± 15.19 s, **...

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Preventive effect of dietary quercetin on disuse muscle atrophy by targeting mitochondria in denervated mice

Cited by 60 publications

References 52 publications

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

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

The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy

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

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