Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function Via the PGC-1α Pathway
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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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Ampelopsin administered for 14 days significantly attenuates dexamethasone-induced muscle atrophy in SD rats by reversing mitochondrial dysfunction, partially mediated by the PGC-1α/Tfam and PGC-1α/mitofusin-2 signaling pathway.
“Moreover, ampelopsin administered for 14 days significantly attenuates dexamethasone-induced muscle atrophy in SD rats by reversing mitochondrial dysfunction, which was partially mediated by the PGC-1α/mitochondrial transcription factor A (Tfam) and PGC-1α/mitofusin-2 signaling pathway [124].”
From Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy (2021) · cites this paper as [124]
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BackgroundSelf-citationFlavonoids: Nutraceutical Potential for Counteracting Muscle Atrophy
Kim, C., & Hwang, J.-K. (2020) · Food Science and Biotechnology · doi:10.1007/s10068-020-00816-5 · Cited by 45 · see citing works
“Besides apoptosis, the overexpression of ROS decreases the production of ATP by suppressing mitochondrial respiratory chain complexes; therefore, reducing oxidative stress has been suggested as a strategy to prevent muscle atrophy (Huang et al., 2018).”
BackgroundInfluentialFucoxanthin rescues dexamethasone induced C2C12 myotubes atrophy
Zhiyin, L., Jinliang, C., Qiunan, C., Yunfei, Y., & Xiao, Q. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111590 · Cited by 46 · see citing works
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“Abbreviations: BrdU, bromodeoxyuridine; GTE, green tea extract; MyoD, myogenic differentiation protein 1; Pax7, paired box 7; SC, satellite cell.”
BackgroundSarcopenic Obesity: Involvement of Oxidative Stress and Beneficial Role of Antioxidant Flavonoids
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“The dexamethasone-induced muscle atrophy in Sprague–Dawley rats was a well-established animal model to find therapeutic agents for muscle atrophy under several wasting conditions [7].”
Geniposide Improves Glucose Homeostasis via Regulating FoxO1/PDK4 in Skeletal Muscle
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Dihydromyricetin Protects Against Gentamicin-Induced Ototoxicity via PGC-1α/SIRT3 Signaling in vitro
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“Previous studies conducted using a C2C12 skeletal muscle cell line have demonstrated that mitochondrial morphological changes occur during mitophagy, a necessary cellular process for removing damaged mitochondria (35,36).”
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Role of acute exacerbations in skeletal muscle impairment in COPD
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Role of Flavonoids in Modulation of Mitochondria Dynamics during Oxidative Stress
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Cold stress causes liver damage by inducing ferroptosis through the p38 MAPK/Drp1 pathway
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“Therefore, there has recently been great interest in therapeutic agents that can prevent muscle atrophy and improve muscle strength [8,9].”
BackgroundTherapeutic Potential of Quercetin as an Antioxidant for Bone-Muscle-Tendon Regeneration and Aging
Kim, J. G., Sharma, A. R., Lee, Y., Chatterjee, S., Choi, Y. J., Rajvansh, R., Chakraborty, C., & Lee, S. (2024) · Aging and Disease · doi:10.14336/ad.2024.0282 · Cited by 24 · see citing works
“Muscle atrophy not only leads to a decrease in muscular function but also hampers the effectiveness of therapies, consequently affecting the overall standard of life and exacerbating both mortality and morbidity rates [87].”
Beneficial Effects of Flavonoids on Skeletal Muscle Health: A Systematic Review and Meta-Analysis
Munguía, L., Ortíz-Flores, M., González, C., Portilla, A., Meaney, E., Villarreal, F. J., Nájera, N., & Ceballos, G. M. (2022) · Journal of Medicinal Food · doi:10.1089/jmf.2021.0054 · Cited by 22 · see citing works
“The most challenging issue in flavonoid use is the broad range of doses used, using ranges between 1 mg/day (using isoflavones and catechins) 25,26 and up to 200 mg/day using dihydromyricetin, 17,27 making it difficult to interpret results in studies and their replication.”
Polyphenol Supplementation and Sarcopenia: A Systematic Review and Meta-Analysis of Clinical Trials
Medoro, A., Scapagnini, G., & Davinelli, S. (2024) · The Journal of Frailty & Aging · doi:10.14283/jfa.2024.73 · Cited by 26 · see citing works
“Moreover, they may reverse mitochondrial dysfunction in skeletal muscle by up-regulating the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling pathway (45, 46).”
Plant Bioactives in the Treatment of Inflammation of Skeletal Muscles: A Molecular Perspective
Karati, D., Varghese, R., Mahadik, K. R., Sharma, R., & Kumar, D. (2022) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2022/4295802 · Cited by 20 · see citing works
“)is condition could be precipitated by a plenitude of conditions, including blast distress, cachexia, chronic kidney disease (CKD), diabetes, high-speed accidents, immobility, obesity, preexisting orthopedic conditions, malnutrition, metabolic acidosis, and sepsis, to name a few [18].”
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“Previous studies reported that DEX accelerates muscle atrophy by inducing mitochondrial dysfunction through decreased mitochondrial content and ATP production in C2C12 myotubes compared to the control [54].”
BackgroundNatural constituents from food sources: potential therapeutic agents against muscle wasting
Shen, S., Yu, H., Gan, L., Yang, Y., & Lin, L. (2019) · Food & Function · doi:10.1039/c9fo00912d · Cited by 20 · see citing works
Rizk, F. H., Soliman, N. A., Kashef, S. M., & Saadany, A. A. E. (2022) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-022-00925-1 · Cited by 16 · see citing works
“[10] who reported that DEX significantly decreased the total body weight, the gastrocnemius and tibialis anterior muscles weights, and the muscle/body weight ratio as well as the muscle strength.”
BackgroundInfluentialJang, J., Koh, J.-H., Kim, Y., Kim, H.-J., Park, S., Chang, Y., Jung, J., Wolfe, R., & Kim, I.-Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179735 · Cited by 14 · see citing works
“Prolonged DEX treatment decreases not only muscle mass, but also mitochondrial content and oxidative capacity in muscle [6], thereby leading to decreases in muscle strength and endurance [7].”
BackgroundKim, J., Kim, H. M., Kim, J. H., Lee, J.-H., Zhang, K., Guo, S., Lee, D. H., Gao, E. M., Son, R. H., Kim, S., et al. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e11597 · Cited by 14 · see citing works
“A previous study reported that DEX inducesmuscle atrophy by promotingmitochondrial dysfunction through decreased ATP production as well as reduced mitochondrial content in C2C12 myotubes compared to the native state [59].”
BackgroundPotential of Lycii Radicis Cortex as an Ameliorative Agent for Skeletal Muscle Atrophy
Son, R. H., Kim, M. I., Kim, H. M., Guo, S., Lee, D. H., Lim, G. M., Kim, S.-M., Kim, J., & Kim, C. Y. (2024) · Pharmaceuticals · doi:10.3390/ph17040462 · Cited by 13 · see citing works
Lee, S.-J., Im, M., Park, S. K., Kim, J. Y., So, E. Y., Liang, O. D., Kang, J., & Bae, G. (2020) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x20500329 · Cited by 13 · see citing works
Ryu, B., Oh, S., Yang, H.-W., Batsukh, S., Chung, D.-M., Seo, M., Park, S., Byun, K., & Jeon, Y. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14040719 · Cited by 11 · see citing works
“In turn, the overwhelmed proteolytic system further accelerates the degradation of skeletal muscle proteins [31].”
BackgroundDing, K., Jiang, W., Zhangwang, J., Wang, Y., Zhang, J., & Lei, M. (2023) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-023-02639-7 · Cited by 11 · see citing works
“Under the guidance of traditional Chinese medicine theory, Cornus officinalis can nourish the liver and kidneys and has been used to treat pain in the back and knees, dizziness, tinnitus, impotence, spermatorrhea, and excessive menstruation Huang et al. 2018a, b).”
BackgroundMethodInfluentialASA VI controls osteoarthritis in mice by maintaining mitochondrial homeostasis through Sirtuin 3
Qiao, J., Zhong, C., Zhang, Q., Yang, G., Li, S., & Jin, J. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112858 · Cited by 8 · see citing works
Self-citation5′-CMP and 5′-UMP alleviate dexamethasone-induced muscular atrophy in C2C12 myotubes
Nakagawara, K., Takeuchi, C., & Ishige, K. (2023) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2023.101460 · Cited by 8 · see citing works
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“Furthermore, DM increases mitochondrial biogenesis, restores mitochondrial function, and enhances protein metabolism, thereby preventing DXM-induced muscle atrophy [218].”
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“Thus, drugs and nutrients that improve mitochondrial function could be ben-e fi cial in preventing those relevant diseases [35].”
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“(cid:129) Group II was the dexamethasone group (DG) or model group that was given dexamethasone at a dose of 0.5 mg/kg for 4 weeks by intraperitoneal injection [23].”
InfluentialAlfarafisa, N. M., Kitaguchi, K., & Yabe, T. (2020) · Reviews in Agricultural Science · doi:10.7831/ras.8.0_70 · Cited by 4 · see citing works
“Besides its role in anti-atrophy, DM also presented a potential role in preventing oxidative damage, through the restoration of mitochondrial function (Huang et al., 2018).”
BackgroundDihydromyricetin protects sevoflurane‐induced mitochondrial dysfunction in HT22 hippocampal cells
Wang, X., Li, H., & Qu, D. (2024) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13912 · Cited by 3 · see citing works
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“Dihydromyricetin ameliorated DEX-induced muscle atrophy by activating PGC-1α and restoring mitochondrial function and mitochondrial bio-genesis (Huang et al., 2018).”
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Protective effects of flaxseed oil against dexamethasone induced skeletal muscle atrophy on rats
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Unveiling the Metabolic Trajectory of Pig Feces Across Different Ages and Senescence
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PDMD: A Comprehensive Repository of Plants Reported for Skeletal Muscle-related Ailments
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“Furthermore, the expression of key regulators of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-g coactivator-1 a (PGC-1 a ), is downregulated (85), leading to a simultaneous decline in both mitochondrial quantity and quality reserves.”
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Özerkliğ, B., Akın, Ş., Olgaz‐Bingol, S., Yıldız, B. O., Powers, S. K., Türkel, İ., & Demirel, H. A. (2026) · Experimental Physiology · doi:10.1113/ep093744
“Consistentwithprevious reports (Huang et al., 2018; Liu et al., 2016), DEX treatment in the pre-sent study resulted in significant reductions in plantaris muscle mass and myofibre CSA.”
- Authors
- Huang, Y., Chen, K., Ren, Q., Yi, L., Zhu, J., Zhang, Q., & Mi, M.
- Affiliations
- Army Medical University (CN)
- Venue
- Cellular Physiology and Biochemistry
- Publisher
- S. Karger AG
- Published
- 2018
- Volume
- 49
- Issue
- 2
- Pages
- 758-779
- ISSN
- 1015-8987 (ISSN-L)
- 1421-9778
- OpenAlex
- W2889179762
- Cited by
- 64
- References
- 84
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 11 · 2023: 9 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 6 · 2018: 1
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular Physiology and Biochemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- dihydromyricetin, dexamethasone, glucocorticoid-induced muscle atrophy, skeletal muscle atrophy, PGC-1α, mitochondrial biogenesis, mitochondrial fusion, mitochondrial dynamics, mitochondrial function, mitochondrial DNA, myofiber cross-sectional area, grip strength, myosin heavy chain, TFAM, mitofusin 2, natural flavonoids
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Dexamethasone, DNA, Mitochondrial, Male, Membrane Proteins, Mitochondria, Muscular Atrophy, Transcription Factors, Signal Transduction, Rats, Sprague-Dawley, GTP Phosphohydrolases, Mitochondrial Proteins, ATP Synthetase Complexes, Myoblasts, RNA Interference, RNA, Small Interfering, Flavonols, Protein Carbonylation, Voltage-Dependent Anion Channel 1, Rats, Membrane Potential, Mitochondrial
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