Mechanisms Underlying the Antifatigue Effects of the Mycelium Extract of Cordyceps (Paecilomyces hepiali, CBG-CS-2) in Mice in the Forced Swimming Test

Read  full  paper  at:

Cordyceps (CS) is used as an alternative medicine and functional food. We examined in vivo mechanisms underlying the antifatigue effects of the cultured mycelium extract of CS (CS extract) in forced swimming mice, a fatigue model that is induced by muscle exercise. Animals orally administered with CS extract significantly extended the loaded forced-swimming time, indicating its antifatigue effects. CS extract modulated the increased levels of blood IL-6 that was induced by forced swimming. CS extract protected the forced swimming-induced increase in NKp46 expression of splenic NK cells, suggesting regulation of fatigue-elicited hyper-reactivity by activated NK cells. By DNA microarray analysis of the quadriceps femoris muscle, it was uncovered that CS extract prevented the forced swimming-mediated upregulation of the expression of 5 genes associating with muscular inflammation (Ccl6, Ccl8, and Wfdc17) and muscle regeneration (Sfrp4 and Nfil3), whereas it regulated the downregulation in the expression of Svs5 participating in actin binding. CS extract exhibits the antifatigue effects through preventing IL-6 accumulation in blood, regulating NK cell activation in the spleen, and alleviating altered expression of genes related to inflammation, regeneration, and actin binding in the local muscle. Thus, CS extract is an effective functional food for preventing fatigue.

Cite this paper

Chae, S. , Mitsunaga, F. , Jung, S. , Ha, K. , Sin, H. , Jang, S. and Nakamura, S. (2015) Mechanisms Underlying the Antifatigue Effects of the Mycelium Extract of Cordyceps (Paecilomyces hepiali, CBG-CS-2) in Mice in the Forced Swimming Test. Food and Nutrition Sciences, 6, 287-298. doi: 10.4236/fns.2015.62029.


[1] Gandevia, S.C. (2001) Spinal and Supraspinal Factors in Human Muscle Fatigue. Physiological Reviews, 81, 17251789.
[2] Bogdanis, G.C. (2012) Effect of Physical Activity and Inactivity on Muscle Fatigue. Frontiers in Physiology, 3, 142.
[3] Finsterer, J. (2012) Biomarkers of Peripheral Muscle Fatigue during Exercise. BMC Musculoskeletal Disorders, 13, 218.
[4] Ren, J., Zhao, M., Wang, H., Cui, C. and You, L. (2011) Effects of Supplementation with Grass Carp Protein versus Peptide on Swimming Endurance in Mice. Nutrition, 27, 789-795.
[5] Shao, J.T., Wang, M.Y. and Zheng, L.B. (2013) Antifatigue Effect of Gracilaria eucheumoides in Mice. Experimental and Therapeutic Medicine, 6, 1512-1516.
[6] Paterson, R.R. (2008) Cordyceps: A Traditional Chinese Medicine and another Fungal Therapeutic Biofactory? Phytochemistry, 69, 1469-1495.
[7] Zhou, X., Gong, Z., Su, Y., Lin, J. and Tang, K. (2009) Cordyceps Fungi: Natural Products, Pharmacological Functions and Developmental Products. The Journal of Pharmacy and Pharmacology, 61, 279-291.
[8] Shin, S., Kwon, J., Lee, S., Kong, H., Lee, S., Lee, C.K., et al. (2010) Immunostimulatory Effects of Cordyceps militaris on Macrophages through the Enhanced Production of Cytokines via the Activation of NF-κB. Immune Network, 10, 55-63.
[9] Li, S.P., Yang, F.Q. and Tsim, K.W.K. (2006) Quality Control of Cordyceps sinensis, a Valued Traditional Chinese Medicine. Journal of Pharmaceutical and Biomedical Analysis, 41, 1571-1584.
[10] Yue, K., Ye, M., Zhou, Z., Sun, W. and Lin, X. (2013) The genus Cordyceps: A Chemical and Pharmacological Review. The Journal of Pharmacy and Pharmacology, 65, 474-493.
[11] Kim, H.O. and Yun, J.W. (2005) A Comparative Study on the Production of Exopolysaccharides between Two Entomopathogenic Fungi Cordyceps militaris and Cordyceps sinensis in Submerged Mycelial Cultures. Journal of Applied Microbiology, 99, 728-738.
[12] Xu, C.P., Sinha, J., Bae, J.T., Kim, S.W. and Yun, J.W. (2006) Optimization of Physical Parameters for Exo-Biopolymer Production in Submerged Mycelial Cultures of Two Entomopathogenic Fungi Paecilomyces japonica and Paecilomyces tenuipes. Letters in Applied Microbiology, 42, 501-506.
[13] Lo, H.C., Hsu, T.H., Tu, S.T. and Lin, K.C. (2006) Anti-Hyperglycemic Activity of Natural and Fermented Cordyceps sinensis in Rats with Diabetes Induced by Nicotinamide and Streptozotocin. The American Journal of Chinese Medicine, 34, 819-832.
[14] Xiao, J.H., Li, Y., Xiao, Y. and Zhong, J.J. (2013) Advance and Prospect of Studies on Bioactivity and Mechanism of Cordyceps Fungi. Zhongguo Zhong Yao Za Zhi, 38, 640-647.
[15] Yan, W., Li, T., Lao, J., Song, B. and Shen, Y. (2013) Anti-Fatigue Property of Cordyceps guangdongensis and the Underlying Mechanisms. Pharmaceutical Biology, 51, 614-620.
[16] Koh, J.H., Kim, K.M., Kim, J.M., Song, J.C. and Suh, H.J. (2003) Antifatigue and Antistress Effect of the Hot-Water Fraction from Mycelia of Cordyceps sinensis. Biological and Pharmaceutical Bulletin, 26, 691-694.
[17] Kumar, R., Negi, P.S., Singh, B., Ilavazhagan, G., Bhargava, K. and Sethy, N.K. (2011) Cordyceps sinensis Promotes Exercise Endurance Capacity of Rats by Activating Skeletal Muscle Metabolic Regulators. Journal of Ethnopharmacology, 136, 260-266.
[18] Jung, K.A., Han, D., Kwon, E.K., Lee, C.H. and Kim, Y.E. (2007) Antifatigue Effect of Rubus coreanus Miquel Extract in Mice. Journal of Medicinal Food, 10, 689-693.
[19] Zhang, X.L., Ren, F., Huang, W., Ding, R.T., Zhou, Q.S. and Liu, X.W. (2010) Anti-Fatigue Activity of Extracts of Stem Bark from Acanthopanax senticosus. Molecules, 16, 28-37.
[20] Jeong, A.R., Nakamura, S. and Mitsunaga, F. (2008) Gene Expression Profile of Th1 and Th2 Cytokines and Their Receptors in Human and Nonhuman Primates. Journal of Medical Primatology, 37, 290-296.
[21] Shippy, R., Fulmer-Smentek, S., Jensen, R.V., Jones, W.D., Wolber, P.K., Johnson, C.D., et al. (2006) Using RNA Sample Titrations to Assess Microarray Platform Performance and Normalization Techniques. Nature Biotechnology, 24, 1123-1131.
[22] Gabrielsson, B.G., Olofsson, L.E., Sjogren, A., Jernas, M., Elander, A., Lonn, M., et al. (2005) Evaluation of Reference Genes for Studies of Gene Expression in Human Adipose Tissue. Obesity Research, 13, 649-652.
[23] Maes, M., Twisk, F.N., Kubera, M. and Ringel, K. (2012) Evidence for Inflammation and Activation of Cell-Mediated Immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Increased Interleukin-1, Tumor Necrosis Factor-α, PMN-Elastase, Lysozyme and Neopterin. Journal of Affective Disorders, 136, 933-939.
[24] Curriu, M., Carrillo, J., Massanella, M., Rigau, J., Alegre, J., Puig, J., et al. (2013) Screening NK-, Band T-Cell Phenotype and Function in Patients Suffering from Chronic Fatigue Syndrome. Journal of Translational Medicine, 11, 68.
[25] Febbraio, M.A. and Pedersen, B.K. (2005) Contraction-Induced Myokine Production and Release: Is Skeletal Muscle an Endocrine Organ? Exercise & Sport Sciences Reviews, 33, 114-119.
[26] Pedersen, B.K. (2007) IL-6 Signaling in Exercise and Disease. Biochemical Society Transactions, 35, 1295-1297.
[27] Moretta, A., Bottino, C., Mingari, M.C., Biassoni, R. and Moretta, L. (2002) What Is a Natural Killer Cell? Nature Immunology, 3, 6-8.
[28] Degli-Esposti, M.A. and Smyth, M.J. (2005) Close Encounters of Different Kinds: Dendritic Cells and NK Cells Take Centre Stage. Nature Reviews Immunology, 5, 112-124.
[29] Stewart, C.A., Vivier, E. and Colonna, M. (2006) Strategies of Natural Killer Cell Recognition and Signaling. Current Topics in Microbiology and Immunology, 298, 1-21.
[30] Mandelboim, O. and Porgador, A. (2001) NKp46. The International Journal of Biochemistry & Cell Biology, 33, 11471150.
[31] Vankayalapati, R., Garg, A., Porgador, A., Griffith, D.E., Klucar, P., Safi, H., et al. (2005) Role of NK Cell-Activating Receptors and Their Ligands in the Lysis of Mononuclear Phagocytes Infected with an Intracellular Bacterium. Journal of Immunology, 175, 4611-4617.
[32] Jonsdottir, I.H. (2000) Exercise Immunology: Neuroendocrine Regulation of NK-Cells. International Journal of Sports Medicine, 21, 20-23.
[33] Wang, J.S. and Weng, T.P. (2011) Hypoxic Exercise Training Promotes Antitumour Cytotoxicity of Natural Killer Cells in Young Men. Clinical Science (London), 121, 343-353.
[34] Gur, C., Porgador, A., Elboim, M., Gazit, R., Mizrahi, S., Stern-Ginossar, N., et al. (2010) The Activating Receptor NKp46 Is Essential for the Development of Type 1 Diabetes. Nature Immunology, 11, 121-128.
[35] Knorr, M., Münzel, T. and Wenzel, P. (2014) Interplay of NK Cells and Monocytes in Vascular Inflammation and Myocardial Infarction. Frontiers in Physiology, 5, 295.
[36] Gan, Y., Liu, Q., Wu, W., Yin, J.X., Bai, X.F., Shen, R., et al. (2014) Ischemic Neurons Recruit Natural Killer Cells that Accelerate Brain Infarction. Proceedings of the National Academy of Sciences of the United States of America, 111, 2704-2709.
[37] Porter, J.D., Guo, W., Merriam, A.P., Khanna, S., Cheng, G., Zhou, X., et al. (2003) Persistent Over-Expression of Specific CC Class Chemokines Correlates with Macrophage and T-Cell Recruitment in mdx Skeletal Muscle. Neuromuscular Disorders, 13, 223-235.
[38] Henningsen, J., Pedersen, B.K. and Kratchmarova, I. (2011) Quantitative Analysis of the Secretion of the MCP Family of Chemokines by Muscle Cells. Molecular BioSystems, 7, 311-321.
[39] Ferreira, Z., Seixas, S., Andrés, A.M., Kretzschmar, W.W., Mullikin, J.C., Cherukuri, P.F., et al. (2013) Reproduction and Immunity-Driven Natural Selection in the Human WFDC Locus. Molecular Biology and Evolution, 30, 938-950.
[40] Zhao, P. and Hoffman, E.P. (2004) Embryonic Myogenesis Pathways in Muscle Regeneration. Developmental Dynamics, 229, 380-392.
[41] Tamboli, R.A., Hajri, T., Jiang, A., Marks-Shulman, P.A., Williams, D.B., Clements, R.H., et al. (2011) Reduction in Inflammatory Gene Expression in Skeletal Muscle from Roux-en-Y Gastric Bypass Patients Randomized to Omentectomy. PLoS ONE, 6, e28577.
[42] Seitz, J. and Aumüller, G. (1990) Biochemical Properties of Secretory Proteins from Rat Seminal Vesicles: Biochemische Eigenschaften sekretorischer Proteine der Ratten-Blaschendrüse. Andrologia, 22, 25-32.
[43] Seitz, J., Keppler, C., Aumüller, G., Polzar, B. and Mannherz, H.G. (1992) SVS II—An Androgen-Dependent Actin-Binding Glycoprotein in Rat Semen. European Journal of Cell Biology, 57, 308-316.        eww150225lx


Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out / 更改 )

Twitter picture

You are commenting using your Twitter account. Log Out / 更改 )

Facebook photo

You are commenting using your Facebook account. Log Out / 更改 )

Google+ photo

You are commenting using your Google+ account. Log Out / 更改 )

Connecting to %s