CYTOKINE AND MATRIX METALLOPROTEINASE PROFILE IN THE SKELETAL MUSCLE OF RATS WITH DIET-INDUCED OBESITY
DOI: http://dx.doi.org/10.30970/sbi.2003.890
Abstract
Background. Our previous studies revealed impaired contractile performance of skeletal muscle in diet-induced obesity, accompanied by intramyocellular lipid accumulation and signs of fibrosis. These findings suggest that obesity-related muscle dysfunction may result from activation of pro-fibrotic pathways and imbalance in extracellular matrix turnover driven by chronic low-grade inflammation – a hallmark of obesity pathogenesis. This study aimed to evaluate the effects of long-term high-fat feeding on the cytokine profile and matrix remodeling markers in rat skeletal muscle and to identify possible biochemical mechanisms underlying obesity-related muscle dysfunction.
Materials and Methods. Adult male Wistar rats were fed either a standard chow (6.7 % fat; 15.27 kJ·g-1) or a high-fat diet (38.8 % fat; 28.71 kJ·g-1) for ten weeks. Serum biochemical parameters (total protein, glucose, cholesterol, bilirubin fractions, urea, creatinine, alanine and aspartate aminotransferases, α-amylase, alkaline phosphatase, γ-glutamyltransferase) were analyzed. Cytokines (TNF-α, IL-6, IL-1β, IL-10, IFN-γ), matrix metalloproteinases (MMP-2, MMP-9), and their inhibitor (TIMP-1) were quantified in skeletal muscle homogenates by ELISA.
Results. A high-fat diet produced pronounced alterations in serum biochemical parameters, reflecting profound metabolic dysregulation and systemic impairment of homeostatic control. In skeletal muscle, obesity induced a significant rise in pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IFN-γ) and a reduction in anti-inflammatory IL-10. These shifts were accompanied by increased MMP-2 and MMP-9 levels and a decline in TIMP-1, suggesting disturbed extracellular matrix turnover and early profibrotic remodeling.
Conclusion. Diet-induced obesity promotes a sustained pro-inflammatory state accompanied by enhanced extracellular matrix remodeling. The imbalance between cytokines, metalloproteinases, and their inhibitor may underlie structural stiffening and decreased contractile efficiency of muscle fibers. A deeper understanding of these cytokine-MMP/TIMP interactions may provide new insights into the mechanisms of obesity-related muscle dysfunction and identify potential targets for maintaining skeletal muscle performance.
Keywords
Full Text:
PDFReferences
| Alameddine, H. S., & Morgan, J. E. (2016). Matrix metalloproteinases and tissue inhibitor of metalloproteinases in inflammation and fibrosis of skeletal muscles. Journal of Neuromuscular Diseases, 3(4), 455-473. doi:10.3233/jnd-160183 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Babaeijandaghi, F., Paiero, A., Long, R., Tung, L. W., Smith, S. P., Cheng, R., Smandych, J., Kajabadi, N., Chang, C.-K., Ghassemi, A., Kennedy, W. D. M., Soliman, H., Schutz, P. W., & Rossi, F. M. V. (2022). TNFα and IFNγ cooperate for efficient pro- to anti-inflammatory transition of macrophages during muscle regeneration. Proceedings of the National Academy of Sciences, 119(44), e2209976119. doi:10.1073/pnas.2209976119 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Bach, D., Naon, D., Pich, S., Soriano, F. X., Vega, N., Rieusset, J., Laville, M., Guillet, C., Boirie, Y., Wallberg-Henriksson, H., Manco, M., Calvani, M., Castagneto, M., Palacín, M., Mingrone, G., Zierath, J. R., Vidal, H., & Zorzano, A. (2005). Expression of Mfn2, the Charcot–Marie–Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes, 54(9), 2685-2693. doi:10.2337/diabetes.54.9.2685 Crossref ● PubMed ● Google Scholar | ||||
| ||||
| Bollinger, L. M. (2017). Potential contributions of skeletal muscle contractile dysfunction to altered biomechanics in obesity. Gait & Posture, 56, 100-107. doi:10.1016/j.gaitpost.2017.05.003 Crossref ● PubMed ● Google Scholar | ||||
| ||||
| Borovkov, S. B., Boiko, V. S., Paliy, A. P., Borovkova, V. M., Pavlichenko, O. V., & Gerilovich, I. O. (2024). Diagnostic significance of biochemical parameters of blood serum of ponies in obesity. Regulatory Mechanisms in Biosystems, 15(4), 856-861. doi:10.15421/0224123 Crossref ● Google Scholar | ||||
| ||||
| Castillo, Í. M. P., Argilés, J. M., Rueda, R., Ramírez, M., & Pedrosa, J. M. L. (2025). Skeletal muscle atrophy and dysfunction in obesity and type-2 diabetes mellitus: myocellular mechanisms involved. Reviews in Endocrine and Metabolic Disorders, 26(5), 815-836. doi:10.1007/s11154-025-09954-9 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Catalán, V., Frühbeck, G., & Gómez-Ambrosi, J. (2018). Inflammatory and oxidative stress markers in skeletal muscle of obese subjects. In G. Frühbeck (Ed.), Obesity: a multidisciplinary approach (pp. 163-189). Elsevier. doi:10.1016/b978-0-12-812504-5.00008-8 Crossref ● Google Scholar | ||||
| ||||
| Cavaliere, G., Cimmino, F., Trinchese, G., Catapano, A., Petrella, L., D'Angelo, M., Lucchin, L., & Mollica, M. P. (2023). From obesity-induced low-grade inflammation to lipotoxicity and mitochondrial dysfunction: altered multi-crosstalk between adipose tissue and metabolically active organs. Antioxidants, 12(6), 1172. doi:10.3390/antiox12061172 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Guo, L., Quan, M., Pang, W., Yin, Y., & Li, F. (2023). Cytokines and exosomal miRNAs in skeletal muscle-adipose crosstalk. Trends in Endocrinology & Metabolism, 34(10), 666-681. doi:10.1016/j.tem.2023.07.006 Crossref ● PubMed ● Google Scholar | ||||
| ||||
| Halenova, T., Raksha, N., Vovk, T., Savchuk, O., Ostapchenko, L., Prylutskyy, Y., Kyzyma, O., Ritter, U., & Scharff, P. (2018). Effect of C60 fullerene nanoparticles on the diet-induced obesity in rats. International Journal of Obesity, 42(12), 1987-1998. doi:10.1038/s41366-018-0016-2 Crossref ● PubMed ● Google Scholar | ||||
| ||||
| Jia, G., & Sowers, J. R. (2019). Increased fibro-adipogenic progenitors and intramyocellular lipid accumulation in obesity-related skeletal muscle dysfunction. Diabetes, 68(1), 18-20. doi:10.2337/dbi18-0047 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Kistner, T. M., Pedersen, B. K., & Lieberman, D. E. (2022). Interleukin 6 as an energy allocator in muscle tissue. Nature Metabolism, 4(2), 170-179. doi:10.1038/s42255-022-00538-4 Crossref ● PubMed ● Google Scholar | ||||
| ||||
| Lee, H., Ha, T. Y., Jung, C. H., Nirmala, F. S., Park, S.-Y., Huh, Y. H., & Ahn, J. (2021). Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice. Journal of Cachexia, Sarcopenia and Muscle, 12(6), 2123-2138. doi:10.1002/jcsm.12794 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Li, Y., Guo, W., Li, H., Wang, Y., Liu, X., & Kong, W. (2024). The change of skeletal muscle caused by inflammation in obesity as the key path to fibrosis: thoughts on mechanisms and intervention strategies. Biomolecules, 15(1), 20. doi:10.3390/biom15010020 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Lin, W., Song, H., Shen, J., Wang, J., Yang, Y., Yang, Y., Cao, J., Xue, L., Zhao, F., Xiao, T., & Lin, R. (2023). Functional role of skeletal muscle-derived interleukin-6 and its effects on lipid metabolism. Frontiers in Physiology, 14, 1110926. doi:10.3389/fphys.2023.1110926 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Mengeste, A. M., Rustan, A. C., & Lund, J. (2021). Skeletal muscle energy metabolism in obesity. Obesity, 29(10), 1582-1595. doi:10.1002/oby.23227 Crossref ● PubMed ● Google Scholar | ||||
| ||||
| Mika, A., & Sledzinski, T. (2016). Alterations of specific lipid groups in serum of obese humans: a review. Obesity Reviews, 18(2), 247-272. doi:10.1111/obr.12475 Crossref ● PubMed ● Google Scholar | ||||
| ||||
| Muñoz-Cánoves, P., Scheele, C., Pedersen, B. K., & Serrano, A. L. (2013). Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? The FEBS Journal, 280(17), 4131-4148. doi:10.1111/febs.12338 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Musale, V., Wasserman, D. H., & Kang, L. (2023). Extracellular matrix remodelling in obesity and metabolic disorders. Life Metabolism, 2(4), load021. doi:10.1093/lifemeta/load021 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Nozdrenko, D. M., Rizun, O. V., Kalmukova, O. O., Kuznietsova, M. Yu., Raksha, N. G., Halenova, T. I., Lynchak, O. V., & Prylutskyy, Yu. I. (2026). Indicators of musculus soleus contractility disorder in obese rats. The Ukrainian Biochemical Journal, 98(1), 88-97. doi:10.15407/ubj98.01.088 Crossref | ||||
| ||||
| Rahemi, H., Nigam, N., & Wakeling, J. M. (2015). The effect of intramuscular fat on skeletal muscle mechanics: implications for the elderly and obese. Journal of the Royal Society Interface, 12(109), 20150365. doi:10.1098/rsif.2015.0365 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Ruiz-Ojeda, F. J., Méndez-Gutiérrez, A., Aguilera, C. M., & Plaza-Díaz, J. (2019). Extracellular matrix remodeling of adipose tissue in obesity and metabolic diseases. International Journal of Molecular Sciences, 20(19), 4888. doi:10.3390/ijms20194888 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Soltis, A. R., Kennedy, N. J., Xin, X., Zhou, F., Ficarro, S. B., Yap, Y. S., Matthews, B. J., Lauffenburger, D. A., White, F. M., Marto, J. A., Davis, R. J., & Fraenkel, E. (2017). Hepatic dysfunction caused by consumption of a high-fat diet. Cell Reports, 21(11), 3317-3328. doi:10.1016/j.celrep.2017.11.059 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Shen, X.-H., Tang, Q.-Y., Huang, J., & Cai, W. (2010). Vitamin E regulates adipocytokine expression in a rat model of dietary-induced obesity. Experimental Biology and Medicine, 235(1), 47-51. doi:10.1258/ebm.2009.009122 Crossref ● PubMed ● Google Scholar | ||||
| ||||
| Toita, R., Kawano, T., Murata, M., & Kang, J. H. (2016). Anti-obesity and anti-inflammatory effects of macrophage-targeted interleukin-10-conjugated liposomes in obese mice. Biomaterials, 110, 81-88. doi:10.1016/j.biomaterials.2016.09.018 Crossref ● PubMed ● Google Scholar | ||||
| ||||
| Wang, L., Wang, Q., Xiong, Y., Shi, W., & Qi, X. (2025). Obesity and its comorbidities: current treatment options, emerging biological mechanisms, future perspectives and challenges. Diabetes, Metabolic Syndrome and Obesity, 18, 3427-3445. doi:10.2147/dmso.s540103 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Webster, J. M., Kempen, L. J. A. P., Hardy, R. S., & Langen, R. C. J. (2020). Inflammation and skeletal muscle wasting during cachexia. Frontiers in Physiology, 11, 597675. doi:10.3389/fphys.2020.597675 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Wiśniewski, K., Choromańska, B., Maciejczyk, M., Dadan, J., & Myśliwiec, P. (2025). Modulating matrix metalloproteinase activity in obesity: comparative effects of bariatric surgery and GLP-1/GIP-based pharmacotherapy. Journal of Clinical Medicine, 14(21), 7648. doi:10.3390/jcm14217648 Crossref ● PubMed ● PMC ● Google Scholar | ||||
| ||||
| Žiberna, L., Jenko-Pražnikar, Z., & Petelin, A. (2021). Serum bilirubin levels in overweight and obese individuals: the importance of anti-inflammatory and antioxidant responses. Antioxidants, 10(9), 1352. doi:10.3390/antiox10091352 Crossref ● PubMed ● PMC ● Google Scholar | ||||
Refbacks
- There are currently no refbacks.
Copyright (c) 2026 Tetiana Halenova, Oleksandr Rizun, Mariana Kuznietsova, Oksana Lynchak, Nataliia Raksha, Yuriy Prylutskyy
This work is licensed under a Creative Commons Attribution 4.0 International License.