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Article

Influence of Intermittent Cold Stimulations on CREB and Its Targeting Genes in Muscle: Investigations into Molecular Mechanisms of Local Cryotherapy

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Laboratory of Laboratory/Sports Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
2
Department of Medical Technology, Faculty of Health Sciences, Tsukuba International University, 6-20-1 Manabe, Tsuchiura, Ibaraki 300-0051, Japan
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Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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Master’s Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
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Laboratory of Environmental Microbiology, Division of Basic Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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Cluster of Medical Sciences, School of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(13), 4588; https://doi.org/10.3390/ijms21134588
Received: 11 May 2020 / Revised: 18 June 2020 / Accepted: 22 June 2020 / Published: 28 June 2020
(This article belongs to the Section Molecular Biology)
Local cryotherapy is widely used as a treatment for sports-related skeletal muscle injuries. The molecular mechanisms are unknown. To clarify these mechanisms, we applied one to three 15-min cold stimulations at 4 °C to various cell lines (in vitro), the tibialis anterior (TA) muscle (ex vivo), and mouse limbs (in vivo). In the in vitro assay, cyclic AMP (cAMP) response element binding protein 1 (CREB1) was markedly phosphorylated (p-CREB1), and the CREB-binding protein (CBP) was recruited to p-CREB-1 in response to two or three cold stimulations. In a reporter assay with the cAMP-responsive element, the signals significantly increased after two to three cold stimulations at 4 °C. In the ex vivo study, CREB-targeting genes were significantly upregulated following two or three cold stimulations. The in vivo experiment disclosed that cold stimulation of a mouse limb for 9 days significantly increased mitochondrial DNA copy number and upregulated genes involved in mitochondrial biogenesis. The results suggest that local cryotherapy increases CREB transcription and upregulates CREB-targeting genes, in a manner dependent on cold stimulation frequency and duration. This information will inform further investigations into local cryotherapy as a treatment for sports-related skeletal muscle trauma. View Full-Text
Keywords: CREB; cryotherapy; gene expression; icing; mitochondria; Pgc-1α; transcription CREB; cryotherapy; gene expression; icing; mitochondria; Pgc-1α; transcription
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MDPI and ACS Style

Sugasawa, T.; Tome, Y.; Takeuchi, Y.; Yoshida, Y.; Yahagi, N.; Sharma, R.; Aita, Y.; Ueda, H.; Maruyama, R.; Takeuchi, K.; Morita, S.; Kawamai, Y.; Takekoshi, K. Influence of Intermittent Cold Stimulations on CREB and Its Targeting Genes in Muscle: Investigations into Molecular Mechanisms of Local Cryotherapy. Int. J. Mol. Sci. 2020, 21, 4588. https://doi.org/10.3390/ijms21134588

AMA Style

Sugasawa T, Tome Y, Takeuchi Y, Yoshida Y, Yahagi N, Sharma R, Aita Y, Ueda H, Maruyama R, Takeuchi K, Morita S, Kawamai Y, Takekoshi K. Influence of Intermittent Cold Stimulations on CREB and Its Targeting Genes in Muscle: Investigations into Molecular Mechanisms of Local Cryotherapy. International Journal of Molecular Sciences. 2020; 21(13):4588. https://doi.org/10.3390/ijms21134588

Chicago/Turabian Style

Sugasawa, Takehito, Yoshiya Tome, Yoshinori Takeuchi, Yasuko Yoshida, Naoya Yahagi, Rahul Sharma, Yuichi Aita, Haruna Ueda, Reina Maruyama, Kaoru Takeuchi, Shohei Morita, Yasushi Kawamai, and Kazuhiro Takekoshi. 2020. "Influence of Intermittent Cold Stimulations on CREB and Its Targeting Genes in Muscle: Investigations into Molecular Mechanisms of Local Cryotherapy" International Journal of Molecular Sciences 21, no. 13: 4588. https://doi.org/10.3390/ijms21134588

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