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Cited by 168Muscle Physiology and DisordersExercise and Physiological ResponsesNutrition and Health in Aging

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Quercetin Protects against Obesity-Induced Skeletal Muscle Inflammation and Atrophy

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Le, Ngoc Hoan, Kim, Chu-Sook, Park, Taesun, Park, Jung Han Yoon, Sung, Mi-Kyung, Lee, Dong Gun, Hong, Sun-Myung, Choe, Suck-Young, Goto, Tsuyoshi, Kawada, Teruo, Yu, Rina·2014·Mediators of Inflammation
DOI 10.1155/2014/834294PMC PMC4295595
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Abstract

Skeletal muscle inflammation and atrophy are closely associated with metabolic impairment such as insulin resistance. Quercetin, a natural polyphenol flavonoid, is known to elicit anti-inflammatory and antioxidant activities. In this study, we investigated its effect on obesity-induced skeletal muscle inflammation and atrophy in mice. Male C57BL/6 mice were fed a regular diet, a high-fat diet (HFD), and an HFD supplemented with quercetin for nine weeks. Quercetin reduced levels of inflammatory cytokines and macrophage accumulation in the skeletal muscle of the HFD-fed obese mice. It also reduced transcript and protein levels of the specific atrophic factors, Atrogin-1 and MuRF1, in the skeletal muscle of the HFD-fed obese mice, and protected against the reduction of muscle mass and muscle fiber size. In vitro, quercetin markedly diminished transcript levels of inflammatory receptors and activation of their signaling molecules (ERK, p38 MAPK, and NF-κB) in cocultured myotubes/macrophages, and this was accompanied by reduced expression of the atrophic factors. Together, these findings suggest that quercetin reduces obesity-induced skeletal muscle atrophy by inhibiting inflammatory receptors and their signaling pathway. Quercetin may be useful for preventing obesity-induced muscle inflammation and sarcopenia.

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Figure 1 Effect of quercetin on obesity-induced inflammatory responses in skeletal muscle. Eight-week-old male C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), or an HFD supplemented with 0.05% quercetin (HFD/Q0.05) or 0.1% quercetin (HFD/Q0.1) for 9 weeks. ((a), (c), (e)) qRT-PCR analysis of cytokine transcripts (TNFα and MCP-1), macrophage markers (F4/80 and CD68), and inflammatory receptors (4-1BB and TLR4) in gastrocnemius muscle. mRNA levels were normalized to the levels of β-actin gene. (b) Protein levels of cytokines TNFα, MCP-1 measured by ELISA. (d) CD68 and α-tubulin were determined by Western blotting. The intensities of the bands were measured densitometrically using ImageJ software. Data are means ± SEM of 6 animals per group. * P < 0.05 and ** P < 0.01 between the HFD and RD groups; † P < 0.05 and †† P < 0.01 between the HFD/Q0.05, HFD/Q0.1 groups and the HFD group.
Figure 1 Effect of quercetin on obesity-induced inflammatory responses in skeletal muscle. Eight-week-old male C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), or an HFD supplemented with 0.05% quercetin (HFD/Q0.05) or 0.1% quercetin (HFD/Q0.1) for 9 weeks. ((a), (c), (e)) qRT-PCR analysis of cytokine transcripts (TNFα and MCP-1), macrophage markers (F4/80 and CD68), and inflammatory receptors (4-1BB and TLR4) in gastrocnemius muscle. mRNA levels were normalized to the levels of β-actin gene. (b) Protein levels of cytokines TNFα, MCP-1 measured by ELISA. (d) CD68 and α-tubulin were determined by Western blotting. The intensities of the bands were measured densitometrically using ImageJ software. Data are means ± SEM of 6 animals per group. * P < 0.05 and ** P < 0.01 between the HFD and RD groups; † P < 0.05 and †† P < 0.01 between the HFD/Q0.05, HFD/Q0.1 groups and the HFD group.CC BY · PubMed Central
Figure 2 Effect of quercetin on obesity-induced skeletal muscle atrophy. (a) Ratios of quadriceps (Quad), gastrocnemius (Gastr), and soleus muscle weights to whole body weight. (b) Mean diameters of gastrocnemius muscle fibers. The diameters were determined with microscope AxioVision software. Five microscopic fields per sample were counted at 200x magnification. (c) qRT-PCR analysis of the expression of atrophic genes Atrogin-1 and MuRF1 in gastrocnemius muscle. Relative mRNA levels were normalized to levels of the β-actin gene. (d) MuRF1 and α-tubulin were determined by Western blotting. The intensities of the bands of MuRF1 and α-tubulin were measured with ImageJ software. Data are means ± SEM of 6 animals per group. ** P < 0.01 and *** P < 0.001 between the HFD and RD groups; † P < 0.05 and †† P < 0.01 between the HFD/Q0.05, HFD/Q0.1, and HFD groups.
Figure 2 Effect of quercetin on obesity-induced skeletal muscle atrophy. (a) Ratios of quadriceps (Quad), gastrocnemius (Gastr), and soleus muscle weights to whole body weight. (b) Mean diameters of gastrocnemius muscle fibers. The diameters were determined with microscope AxioVision software. Five microscopic fields per sample were counted at 200x magnification. (c) qRT-PCR analysis of the expression of atrophic genes Atrogin-1 and MuRF1 in gastrocnemius muscle. Relative mRNA levels were normalized to levels of the β-actin gene. (d) MuRF1 and α-tubulin were determined by Western blotting. The intensities of the bands of MuRF1 and α-tubulin were measured with ImageJ software. Data are means ± SEM of 6 animals per group. ** P < 0.01 and *** P < 0.001 between the HFD and RD groups; † P < 0.05 and †† P < 0.01 between the HFD/Q0.05, HFD/Q0.1, and HFD groups.CC BY · PubMed Central
Figure 3 Quercetin suppresses inflammatory responses in cocultured myotubes and macrophages treated with FFA. C2C12 myotubes (Mb) were cocultured with Raw264.7 macrophages (M⌀) for 24 h (Co) and then treated with 500 μM palmitic acid for the next 24 h (Co/FFA). As the control, the same numbers of Mb and M⌀ were cultured separately and mixed after being collected/harvested, named as mixture (Mix), same as FFA treated condition, which was named as Mix/FFA. The established Mb and M⌀ were pretreated with 50 μM quercetin in serum-free DMEM for 1 h (Co/FFA/Q). ((a), (c)) qRT-PCR analysis of transcripts of inflammatory cytokines (TNFα and MCP-1) and inflammatory receptors (4-1BB and TLR4). (b) Protein levels of TNFα and MCP-1 released into the culture medium were measured by ELISA. (d) Phosphorylated ERK, ERK, phosphorylated p38 MAPK, p38 MAPK, IκBα, and α-tubulin were determined by Western blotting. (e) The intensities of the bands were measured using ImageJ. Data are means ± SEM of three independent triplicate experiments. * P < 0.05, ** P < 0.01, and *** P < 0.001 for the differences between the Co/FFA group and the Mix, Mix/FFA, or Co groups. † P < 0.05 and †† P < 0.01 for the differences between the Co/FFA/Q and Co/FFA groups.
Figure 3 Quercetin suppresses inflammatory responses in cocultured myotubes and macrophages treated with FFA. C2C12 myotubes (Mb) were cocultured with Raw264.7 macrophages (M⌀) for 24 h (Co) and then treated with 500 μM palmitic acid for the next 24 h (Co/FFA). As the control, the same numbers of Mb and M⌀ were cultured separately and mixed after being collected/harvested, named as mixture (Mix), same as FFA treated condition, which was named as Mix/FFA. The established Mb and M⌀ were pretreated with 50 μM quercetin in serum-free DMEM for 1 h (Co/FFA/Q). ((a), (c)) qRT-PCR analysis of transcripts of inflammatory cytokines (TNFα and MCP-1) and inflammatory receptors (4-1BB and TLR4). (b) Protein levels of TNFα and MCP-1 released into the culture medium were measured by ELISA. (d) Phosphorylated ERK, ERK, phosphorylated p38 MAPK, p38 MAPK, IκBα, and α-tubulin were determined by Western blotting. (e) The intensities of the bands were measured using ImageJ. Data are means ± SEM of three independent triplicate experiments. * P < 0.05, ** P < 0.01, and *** P < 0.001 for the differences between the Co/FFA group and the Mix, Mix/FFA, or Co groups. † P < 0.05 and †† P < 0.01 for the differences between the Co/FFA/Q and Co/FFA groups.CC BY · PubMed Central
Figure 4 Quercetin suppresses the expression of atrophic factors in cocultured myotubes and macrophages treated with FFA. C2C12 Mb were cocultured with M⌀ for 24 h and then treated with 500 μM FFA for the next 24 h. Quercetin (50 μM) was added for 1 h before coculture started, and DMSO was used as control. (a) qRT-PCR analysis of transcripts of atrophic genes, including Atrogin-1 and MuRF1. (b) Expressions of MuRF1 and α-tubulin were determined by Western blotting. The intensities of the bands were measured using ImageJ software. Data are means ± SEM of three independent triplicate experiments. ** P < 0.01 for the differences between the Co/FFA group and the Mix, Mix/FFA, or Co groups. † P < 0.05 and †† P < 0.01 for the differences between the Co/FFA/Q and Co/FFA groups.
Figure 4 Quercetin suppresses the expression of atrophic factors in cocultured myotubes and macrophages treated with FFA. C2C12 Mb were cocultured with M⌀ for 24 h and then treated with 500 μM FFA for the next 24 h. Quercetin (50 μM) was added for 1 h before coculture started, and DMSO was used as control. (a) qRT-PCR analysis of transcripts of atrophic genes, including Atrogin-1 and MuRF1. (b) Expressions of MuRF1 and α-tubulin were determined by Western blotting. The intensities of the bands were measured using ImageJ software. Data are means ± SEM of three independent triplicate experiments. ** P < 0.01 for the differences between the Co/FFA group and the Mix, Mix/FFA, or Co groups. † P < 0.05 and †† P < 0.01 for the differences between the Co/FFA/Q and Co/FFA groups.CC BY · PubMed Central
Figure 5 Schematic representation of the effect of quercetin on obesity-induced skeletal muscle inflammation and muscle atrophy. Obesity leads to infiltration of macrophages and increases FFA in skeletal muscle. Macrophages release inflammatory cytokines and/or directly contact muscle cells, leading to activation of inflammatory signaling pathways, which are also induced by binding of FFA to TLRs. The inflammatory signaling pathway induces expression of atrogenes. This leads to loss of muscle mass, and these changes ultimately contribute to local and systemic insulin resistance. Quercetin inhibits macrophage infiltration and activation of inflammatory pathways, leading to diminished expression of atrophic genes.
Figure 5 Schematic representation of the effect of quercetin on obesity-induced skeletal muscle inflammation and muscle atrophy. Obesity leads to infiltration of macrophages and increases FFA in skeletal muscle. Macrophages release inflammatory cytokines and/or directly contact muscle cells, leading to activation of inflammatory signaling pathways, which are also induced by binding of FFA to TLRs. The inflammatory signaling pathway induces expression of atrogenes. This leads to loss of muscle mass, and these changes ultimately contribute to local and systemic insulin resistance. Quercetin inhibits macrophage infiltration and activation of inflammatory pathways, leading to diminished expression of atrophic genes.CC BY · PubMed Central

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Authors
Le, N. H., Kim, C.-S., Park, T., Park, J. H. Y., Sung, M.-K., Lee, D. G., Hong, S.-M., Choe, S.-Y., Goto, T., Kawada, T., & Yu, R.
Affiliations
  • Department of Food Science and Nutrition, University of Ulsan, Ulsan 680-749, Republic of Korea
  • University of Ulsan (KR)
  • Yonsei University (KR)
  • Hallym University (KR)
  • Sookmyung Women's University (KR)
  • Kyungpook National University (KR)
  • Kyoto University (JP)
Corresponding author
Yu, Rina
ORCID
Venue
Mediators of Inflammation
Publisher
Wiley
Published
2014
Volume
2014
Pages
1-10
ISSN
  • 0962-9351 (ISSN-L)
  • 1466-1861
DOI
10.1155/2014/834294
PMC
PMC4295595
OpenAlex
W2159198268
Cited by
167
References
41
Citations by year
2026: 13 · 2025: 20 · 2024: 16 · 2023: 16 · 2022: 18 · 2021: 20 · 2020: 10 · 2019: 19 · 2018: 12 · 2017: 11 · 2016: 9 · 2015: 3
FWCI
3.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Mediators of Inflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Research Foundation of Korea (2012R1A2A4A01002702)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
  • Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
Keywords
quercetin, obesity, skeletal muscle atrophy, muscle inflammation, sarcopenia, high-fat diet, inflammatory cytokines, macrophage accumulation, atrogin-1, MuRF1, NF-κB signaling, MAPK signaling, myotubes, flavonoids, insulin resistance
MeSH terms
Tripartite Motif Proteins, Animals, Antioxidants, Atrophy, Base Sequence, Cell Line, Inflammation, Insulin Resistance, Macrophages, Male, Mice, Inbred C57BL, Muscle Proteins, Obesity, Quercetin, Signal Transduction, Cytokines, Muscle, Skeletal, Ubiquitin-Protein Ligases, SKP Cullin F-Box Protein Ligases, Mice, Sarcopenia

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